A comprehensive AI model development framework for consistent Gleason grading.

BACKGROUND: Artificial Intelligence(AI)-based solutions for Gleason grading hold promise for pathologists, while image quality inconsistency, continuous data integration needs, and limited generalizability hinder their adoption and scalability. METHODS: We present a comprehensive digital pathology workflow for AI-assisted Gleason grading. It incorporates A!MagQC (image quality control), A!HistoClouds (cloud-based annotation), Pathologist-AI Interaction (PAI) for continuous model improvement, Trained on Akoya-scanned images only, the model utilizes color augmentation and image appearance migration to address scanner variations. We evaluate it on Whole Slide Images (WSI) from another five scanners and conduct validations with pathologists to assess AI efficacy and PAI. RESULTS: Our model achieves an average F1 score of 0.80 on annotations and 0.71 Quadratic Weighted Kappa on WSIs for Akoya-scanned images. Applying our generalization solution increases the average F1 score for Gleason pattern detection from 0.73 to 0.88 on images from other scanners. The model accelerates Gleason scoring time by 43% while maintaining accuracy. Additionally, PAI improve annotation efficiency by 2.5 times and led to further improvements in model performance. CONCLUSIONS: This pipeline represents a notable advancement in AI-assisted Gleason grading for improved consistency, accuracy, and efficiency. Unlike previous methods limited by scanner specificity, our model achieves outstanding performance across diverse scanners. This improvement paves the way for its seamless integration into clinical workflows.

Gleason grading is a well-accepted diagnostic standard to assess the severity of prostate cancer in patients' tissue samples, based on how abnormal the cells in their prostate tumor look under a microscope. This process can be complex and time-consuming. We explore how artificial intelligence (AI) can help pathologists perform Gleason grading more efficiently and consistently. We build an AI-based system which automatically checks image quality, standardizes the appearance of images from different equipment, learns from pathologists' feedback, and constantly improves model performance. Testing shows that our approach achieves consistent results across different equipment and improves efficiency of the grading process. With further testing and implementation in the clinic, our approach could potentially improve prostate cancer diagnosis and management.

Artificial intelligence-assisted quantification and assessment of whole slide images for pediatric kidney disease diagnosis.

MOTIVATION: Pediatric kidney disease is a widespread, progressive condition that severely impacts growth and development of children. Chronic kidney disease is often more insidious in children than in adults, usually requiring a renal biopsy for diagnosis. Biopsy evaluation requires copious examination by trained pathologists, which can be tedious and prone to human error. In this study, we propose an artificial intelligence (AI) method to assist pathologists in accurate segmentation and classification of pediatric kidney structures, named as AI-based Pediatric Kidney Diagnosis (APKD). RESULTS: We collected 2935 pediatric patients diagnosed with kidney disease for the development of APKD. The dataset comprised 93 932 histological structures annotated manually by three skilled nephropathologists. APKD scored an average accuracy of 94% for each kidney structure category, including 99% in the glomerulus. We found strong correlation between the model and manual detection in detected glomeruli (Spearman correlation coefficient r = 0.98, P < .001; intraclass correlation coefficient ICC = 0.98, 95% CI = 0.96-0.98). Compared to manual detection, APKD was approximately 5.5 times faster in segmenting glomeruli. Finally, we show how the pathological features extracted by APKD can identify focal abnormalities of the glomerular capillary wall to aid in the early diagnosis of pediatric kidney disease. AVAILABILITY AND IMPLEMENTATION: https://github.com/ChunyueFeng/Kidney-DataSet.

Automatic DNA replication tract measurement to assess replication and repair dynamics at the single-molecule level.

MOTIVATION: DNA fibre assay has a potential application in genomic medicine, cancer and stem cell research at the single-molecule level. A major challenge for the clinical and research implementation of DNA fibre assays is the slow speed in which manual analysis takes place as it limits the clinical actionability. While automatic detection of DNA fibres speeds up this process considerably, current publicly available software have limited features in terms of their user interface for manual correction of results, which in turn limit their accuracy and ability to account for atypical structures that may be important in diagnosis or investigative studies. We recognize that core improvements can be made to the GUI to allow for direct interaction with automatic results to preserve accuracy as well as enhance the versatility of automatic DNA fibre detection for use in variety of situations. RESULTS: To address the unmet needs of diverse DNA fibre analysis investigations, we propose DNA Stranding, an open-source software that is able to perform accurate fibre length quantification (13.22% mean relative error) and fibre pattern recognition (R > 0.93) with up to six fibre patterns supported. With the graphical interface, we developed, user can conduct semi-automatic analyses which benefits from the advantages of both automatic and manual processes to improve workflow efficiency without compromising accuracy. AVAILABILITY AND IMPLEMENTATION: The software package is available at https://github.com/lgole/DNAStranding. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Gathering Health Perspectives of the Justice Involved: A Multisite Needs Assessment Survey.

The well-being of justice-involved individuals must be of high priority to achieve health equity, reduce health disparities, and improve community health. To better understand the health interests and needs of justice-involved individuals, a survey was administered inquiring about health information-seeking behavior and health topics of interest. The survey was administered using secure tablet computers and completed by 1,888 incarcerated participants in 35 jails in 17 states. Salient themes that emerged from this research include the relatively equal use of the internet and health care providers as resources for health information; the extensive interest in learning about multiple health care topics; and demographic variations in health information-seeking behaviors and health topics of interest. Tailoring correctional health education programs to coincide with the interests and needs of the justice-involved population may attract more participants and thus result in better self-care management skills and health outcomes upon reentering communities.

Detection of subtle white matter lesions in MRI through texture feature extraction and boundary delineation using an embedded clustering strategy.

White matter lesions (WML) underlie multiple brain disorders, and automatic WML segmentation is crucial to evaluate the natural disease course and effectiveness of clinical interventions, including drug discovery. Although recent research has achieved tremendous progress in WML segmentation, accurate detection of subtle WML present early in the disease course remains particularly challenging. Here we propose an approach to automatic WML segmentation of mild WML loads using an intensity standardisation technique, gray level co-occurrence matrix (GLCM) embedded clustering technique, and random forest (RF) classifier to extract texture features and identify morphology specific to true WML. We precisely define their boundaries through a local outlier factor (LOF) algorithm that identifies edge pixels by local density deviation relative to its neighbors. The automated approach was validated on 32 human subjects, demonstrating strong agreement and correlation (excluding one outlier) with manual delineation by a neuroradiologist through Intra-Class Correlation (ICC = 0.881, 95% CI 0.769, 0.941) and Pearson correlation (r = 0.895, p-value < 0.001), respectively, and outperforming three leading algorithms (Trimmed Mean Outlier Detection, Lesion Prediction Algorithm, and SALEM-LS) in five of the six established key metrics defined in the MICCAI Grand Challenge. By facilitating more accurate segmentation of subtle WML, this approach may enable earlier diagnosis and intervention.

Comprehensive literature review on the radiographic findings, imaging modalities, and the role of radiology in the COVID-19 pandemic.

Since the outbreak of the coronavirus disease 2019 (COVID-19) pandemic, over 103214008 cases have been reported, with more than 2231158 deaths as of January 31, 2021. Although the gold standard for diagnosis of this disease remains the reverse-transcription polymerase chain reaction of nasopharyngeal and oropharyngeal swabs, its false-negative rates have ignited the use of medical imaging as an important adjunct or alternative. Medical imaging assists in identifying the pathogenesis, the degree of pulmonary damage, and the characteristic features in each imaging modality. This literature review collates the characteristic radiographic findings of COVID-19 in various imaging modalities while keeping the preliminary focus on chest radiography, computed tomography (CT), and ultrasound scans. Given the higher sensitivity and greater proficiency in detecting characteristic findings during the early stages, CT scans are more reliable in diagnosis and serve as a practical method in following up the disease time course. As research rapidly expands, we have emphasized the CO-RADS classification system as a tool to aid in communicating the likelihood of COVID-19 suspicion among healthcare workers. Additionally, the utilization of other scoring systems such as MuLBSTA, Radiological Assessment of Lung Edema, and Brixia in this pandemic are reviewed as they integrate the radiographic findings into an objective scoring system to risk stratify the patients and predict the severity of disease. Furthermore, current progress in the utilization of artificial intelligence via radiomics is evaluated. Lastly, the lesson from the first wave and preparation for the second wave from the point of view of radiology are summarized.

Constructing and optimizing 3D atlases from 2D data with application to the developing mouse brain.

3D imaging data necessitate 3D reference atlases for accurate quantitative interpretation. Existing computational methods to generate 3D atlases from 2D-derived atlases result in extensive artifacts, while manual curation approaches are labor-intensive. We present a computational approach for 3D atlas construction that substantially reduces artifacts by identifying anatomical boundaries in the underlying imaging data and using these to guide 3D transformation. Anatomical boundaries also allow extension of atlases to complete edge regions. Applying these methods to the eight developmental stages in the Allen Developing Mouse Brain Atlas (ADMBA) led to more comprehensive and accurate atlases. We generated imaging data from 15 whole mouse brains to validate atlas performance and observed qualitative and quantitative improvement (37% greater alignment between atlas and anatomical boundaries). We provide the pipeline as the MagellanMapper software and the eight 3D reconstructed ADMBA atlases. These resources facilitate whole-organ quantitative analysis between samples and across development.

The research community needs precise, reliable 3D atlases of organs to pinpoint where biological structures and processes are located. For instance, these maps are essential to understand where specific genes are turned on or off, or the spatial organization of various groups of cells over time. For centuries, atlases have been built by thinly 'slicing up' an organ, and then precisely representing each 2D layer. Yet this approach is imperfect: each layer may be accurate on its own, but inevitable mismatches appear between the slices when viewed in 3D or from another angle. Advances in microscopy now allow entire organs to be imaged in 3D. Comparing these images with atlases could help to detect subtle differences that indicate or underlie disease. However, this is only possible if 3D maps are accurate and do not feature mismatches between layers. To create an atlas without such artifacts, one approach consists in starting from scratch and manually redrawing the maps in 3D, a labor-intensive method that discards a large body of well-established atlases. Instead, Young et al. set out to create an automated method which could help to refine existing 'layer-based' atlases, releasing software that anyone can use to improve current maps. The package was created by harnessing eight atlases in the Allen Developing Mouse Brain Atlas, and then using the underlying anatomical images to resolve discrepancies between layers or fill out any missing areas. Known as MagellanMapper, the software was extensively tested to demonstrate the accuracy of the maps it creates, including comparison to whole-brain imaging data from 15 mouse brains. Armed with this new software, researchers can improve the accuracy of their atlases, helping them to understand the structure of organs at the level of the cell and giving them insight into a broad range of human disorders.

Preventing Recurrence in Clean and Contaminated Hernias Using Biologic Versus Synthetic Mesh in Ventral Hernia Repair: The PRICE Randomized Clinical Trial.

OBJECTIVE: The aim of this study was to evaluate which mesh type yields lower recurrence and complication rates after ventral hernia repair. SUMMARY BACKGROUND DATA: More than 400,000 ventral hernia repairs are performed annually in the United States. Although the most effective method for repairing ventral hernias involves using mesh, whether to use biologic mesh versus synthetic mesh is controversial. METHODS: Single-blind, randomized, controlled, pragmatic clinical trial conducted from March 2014 through October 2018; 165 patients enrolled with an average follow up of 26 months. Patients were randomized 1:1 to have their ventral hernias repaired using either a biologic (porcine) or synthetic (polypropylene) mesh. The primary study outcome measure was hernia recurrence at 2 years. RESULTS: A total of 165 patients (68 men), mean age 55 years, were included in the study with a mean follow-up of 26 months. An intention-to-treat analysis noted that hernias recurred in 25 patients (39.7%) assigned to biologic mesh and in 14 patients (21.9%) assigned to synthetic mesh (P = 0.035) at 2 years. Subgroup analysis identified an increased rate of hernia recurrence in the biologic versus the synthetic mesh group under contaminated wound conditions (50.0% vs 5.9%; P for interaction = 0.041). Postoperative complication rates were similar for the 2 mesh types. CONCLUSIONS: The risk of hernia recurrence was significantly higher for patients undergoing ventral hernia repair with biologic mesh compared to synthetic mesh, with similar rates of postoperative complications. These data indicate that the use of synthetic mesh over biologic mesh to repair ventral hernias is effective and can be endorsed, including under contaminated wound conditions. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02041494.

Satellite cell activation and retention of muscle regenerative potential after long-term denervation.

Irreversible denervation atrophy remains an unsolved clinical problem, and the role of skeletal muscle stem cell (MuSC, satellite cell) depletion in this process is unclear. We investigated the ability of MuSCs to regenerate muscle in the context of denervation. Three to 12 months following sciatic denervation in mice, MuSC number, size, EdU uptake, rate of division, and mitochondrial activity were increased. Following acute myotoxin injury, denervated muscles formed new muscle fibers in situ. MuSCs isolated via flow cytometry from denervated mouse muscle, or from atrophic denervated gluteus maximus muscles of humans with complete spinal cord injuries two decades prior, formed new muscle fibers and reoccupied the anatomic niche after transplantation into uninjured muscle. Our results show unequivocally that, even after prolonged denervation, MuSCs retain intrinsic regenerative potential similar to that of uninjured MuSCs. Treatment of denervation atrophy will require elucidating the non-MuSC environmental changes in muscle that prevent functional regeneration.

Whole-Brain Image Analysis and Anatomical Atlas 3D Generation Using MagellanMapper.

MagellanMapper is a software suite designed for visual inspection and end-to-end automated processing of large-volume, 3D brain imaging datasets in a memory-efficient manner. The rapidly growing number of large-volume, high-resolution datasets necessitates visualization of raw data at both macro- and microscopic levels to assess the quality of data, as well as automated processing to quantify data in an unbiased manner for comparison across a large number of samples. To facilitate these analyses, MagellanMapper provides both a graphical user interface for manual inspection and a command-line interface for automated image processing. At the macroscopic level, the graphical interface allows researchers to view full volumetric images simultaneously in each dimension and to annotate anatomical label placements. At the microscopic level, researchers can inspect regions of interest at high resolution to build ground truth data of cellular locations such as nuclei positions. Using the command-line interface, researchers can automate cell detection across volumetric images, refine anatomical atlas labels to fit underlying histology, register these atlases to sample images, and perform statistical analyses by anatomical region. MagellanMapper leverages established open-source computer vision libraries and is itself open source and freely available for download and extension. © 2020 Wiley Periodicals LLC. Basic Protocol 1: MagellanMapper installation Alternate Protocol: Alternative methods for MagellanMapper installation Basic Protocol 2: Import image files into MagellanMapper Basic Protocol 3: Region of interest visualization and annotation Basic Protocol 4: Explore an atlas along all three dimensions and register to a sample brain Basic Protocol 5: Automated 3D anatomical atlas construction Basic Protocol 6: Whole-tissue cell detection and quantification by anatomical label Support Protocol: Import a tiled microscopy image in proprietary format into MagellanMapper.

Silver microparticles plus fibrin tissue sealant prevents incisional hernias in rats.

BACKGROUND: Open abdominal surgery is frequently complicated by the subsequent development of an incisional hernia. Consequently, more than 400,000 incisional hernia repairs are performed each year, adding over $15 billion per year to U.S. health-care expenditures. While the vast majority of studies have focused on improved surgical techniques or prosthetic materials, we examined the use of metallic silver microparticles to prevent incisional hernia formation through enhanced wound healing. MATERIALS AND METHODS: A rodent incisional hernia model was used. Eighty-two rats were randomly placed into two control groups (saline alone and silver microparticles alone), and three experimental groups (0 mg/cm, 2.5 mg/cm, and 25 mg/cm of silver microparticles applied with a fibrin sealant). Incisional hernia incidence and size, tensile strength, and tissue histology were assessed after 28 days. RESULTS: A significant reduction of both incisional hernia incidence and hernia size was observed between the control groups and 2.5 mg/cm group, and between the control and 25 mg/cm group by nearly 60% and 90%, respectively (P < 0.05). Histological samples showed a noticeable increase in new fibrosis in the treated animals as compared with the controls, whereas the tensile strength between the groups did not differ. CONCLUSIONS: The novel approach of using silver microparticles to enhance wound healing appears to be a safe and effective method to prevent incisional hernias from developing and could herald a new era of medicinal silver use.

Contemporary concepts in hernia prevention: Selected proceedings from the 2017 International Symposium on Prevention of Incisional Hernias.

Incisional hernia is a frequent complication of midline laparotomy and enterostomal creation and is associated with high morbidity, decreased quality of life, and high costs. The International Symposium on Incisional Hernia Prevention was held October 19-20, 2017, at the InterContinental Hotel in San Francisco, CA, hosted by the Department of Surgery, University of California, San Francisco. One hundred and three attendees included general and plastic surgeons from 9 countries, including principal participants for several of the seminal studies in the field. Over the course of the 2-day meeting, there were 38 oral presentations, 3 keynote lectures, and 2 panel discussions. The Symposium was a combination of new information but also a comprehensive review of the existing data so as to assess the current state of the field and to set the stage for future research. Further, the Symposium sought to increase awareness and thus emphasize the importance of preventing the formation of incisional and enterostomal hernias.

Biopolymer Molecular Weight Can Modulate the Wound Healing Efficacy of Multivalent Sonic Hedgehog-Hyaluronic Acid Conjugates.

There is a clinical need for new therapeutics to improve healing of chronic impaired wounds. Thus, we investigated how biopolymer conjugation could be used to improve the wound healing performance of a key growth factor for tissue regeneration: Sonic hedgehog (Shh). We generated two multivalent Shh conjugates (mvShh) using hyaluronic acid with two different MWs, which exhibited equivalent potency and proteolytic protection in vitro. Using db/db diabetic mice, we showed that mvShh made with smaller HyA MW resulted in more rapid and robust neovascularization compared to mvShh made with larger MW HyA. Further, smaller mvShh conjugates resulted in faster wound resolution compared to the unconjugated Shh. This study is the first to show how the wound healing efficacy of multivalent protein-polymer conjugates is sensitive to the polymer MW, and our findings suggest that this parameter could be used to enhance the efficacy of growth factor conjugates.

Klotho mice: a novel wound model of aged skin.

BACKGROUND: As the elderly population continues to expand, it becomes increasingly important to develop treatments to improve wound healing in the elderly. One problem limiting the research is the lack of appropriate animal models for wound healing in elderly patients. We hypothesized that the Klotho mouse of premature aging is a suitable animal model to shed light on many of the biological processes involved in aging skin. METHODS: Klotho mice (kl/kl), Klotho-heterozygous mice (kl/+), and wild-type mice (+/+) were wounded, and the area of the wound was measured every 3 days until the wound was healed. To compare the klotho phenotype with wild-type mice, wounds were also harvested at 4 and 7 days after wounding. For histological examination, paraffin-embedded sections were stained with hematoxylin and eosin and Masson trichrome. Collagen expression in the wound was also studied by analyzing messenger RNA using real-time polymerase chain reaction. RESULTS: Klotho mice showed a significantly slower rate of wound closure compared with Klotho-heterozygous mice and wild-type mice. Histology showed substantial less healing and collagen deposition in the wounds of the Klotho mice. The expression of collagen messenger RNA in Klotho mice was also less than that in heterozygous and wild-type mice. The Klotho mice exhibited significant phenotypic similarities with aged skin, such as atrophy and delayed wound healing. CONCLUSION: These preliminary data suggest that the Klotho mouse may be a model to further investigate wound healing in the elderly.

The effects of immunosuppressive medications on outcomes in microvascular free tissue transfer.

BACKGROUND: Reported 10-year patient survival after liver transplantation is nearing 70 percent, with similar trends seen for kidney transplantation. With increasing life expectancy, these patients have an increased need for posttransplant reconstructive surgery. Thus, plastic surgeons must know the effects of immunosuppressive medications on outcomes in microvascular reconstruction. METHODS: A retrospective review was performed on all immunosuppressed solid-organ transplant patients who underwent subsequent free tissue transfer of all types, over an 8-year period. Patient demographics, type of solid organ transplant, immunosuppressive regimen, anticoagulation regimen, associated medical comorbidities, and complication rates were analyzed. RESULTS: Twenty-four microvascular free tissue transfers were performed over an 8-year period on immunosuppressed patients, for head and neck and lower extremity reconstruction. Fifteen patients (63 percent) underwent prior kidney transplant, seven (29 percent) underwent prior liver transplant, and two (8 percent) underwent prior lung transplant. Prednisone (79 percent of patients), cyclosporine (33 percent), and tacrolimus (33 percent) were the most commonly used immunosuppressive medications. Complications included one total flap loss (4 percent), three intraoperative arterial thromboses (13 percent), and two postoperative venous thromboses (8 percent). Univariate analysis illustrated a statistically significant association between prednisone and overall complication rate (p = 0.032). CONCLUSIONS: Microvascular free tissue transfer is a challenge in immunosuppressed patients. Univariate analysis showed prednisone to correlate statistically with operative morbidity. Transplant patients receiving prednisone at the time of their elective free flap procedure will require additional care to lower the additional risk of delayed wound healing, partial flap loss, and anastomotic thrombosis. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic IV.

Application of the chemokine CXCL12 expression plasmid restores wound healing to near normal in a diabetic mouse model.

BACKGROUND: CXCL12 is a chemokine involved in postinjury leukocyte chemotaxis, migration, and homing of stem cells. We hypothesized that by increasing the level of the chemokine CXCL12 in wounds of diabetic mice, we would increase stem cell recruitment to the wound and, thus, accelerate time to wound closure. METHODS: Eighteen Lepr db-/db- (B6.Cg-m +/+ Leprdb/J; Jackson Labs, Bar Harbor, ME) and their nondiabetic littermates were wounded and treated either with an empty plasmid or a plasmid containing the CXCL12 gene. Wounds were measured approximately every 5 days until they closed completely and were analyzed using planimetry. Wounds were harvested, and relative expression of CXCL12 mRNA was measured using an ABI Prism SDS 7000. To study stem cells affected by this, the plasmid's affect on stem cell recruitment, we used flow cytometry. RESULTS: The diabetic wounds contain a significantly decreased level of CXCL12 mRNA at day 7 postwounding, and these wounds take 55 days to heal. Application of a CXCL12 plasmid to diabetic wounds significantly increases CXCL12 mRNA at day 7, and these wounds heal in 23 days. CONCLUSIONS: Lack of CXCL12 in diabetic wounds contributes to delayed wound healing and can be reversed via single application of a CXCL12-containing plasmid.

Altered ultrasonic vocalizations in a tuberous sclerosis mouse model of autism.

Tuberous sclerosis (TSC) is an autosomally dominant neurocutaneous disease notable for its high comorbidity with autism in human patients. Studies of murine models of tuberous sclerosis have found defects in cognition and learning, but thus far have not uncovered deficits in social behaviors relevant to autism. To explore social communication and interaction in TSC2 heterozygous mice, we recorded ultrasonic vocalizations (USV) and found that although both wild-type (WT) and heterozygous pups born to WT dams showed similar call rates and patterns, baseline vocalization rates were elevated in pups born to heterozygous dams. Further analysis revealed several robust features of maternal potentiation in all but WT pups born to heterozygous dams. This lack of potentiation is suggestive of defects in mother-pup social interaction during or before the reunion period between WT pups and heterozygous dams. Intriguingly, male pups of both genotypes born to heterozygous dams showed particularly heightened call rates and burst patterns. Because our maternal retrieval experiments revealed that TSC2(+/-) dams exhibited improved defensive reactions against intruders and highly efficient pup retrieval performance, the alterations in their pups' USVs and maternal potentiation do not appear to result from poor maternal care. These findings suggest that a pup's interaction with its mother strongly influences the pup's vocal communication, revealing an intriguing dependence of this social behavior on TSC2 gene dosage of both parties involved. Our study of this murine model thus uncovers social abnormalities that arise from TSC haploinsufficiency and are suggestive of autism.

Open incisional hernia repair at an academic tertiary care medical center.

OBJECTIVE: To describe the postoperative complication rates of a large consecutive series of patients who underwent open incisional ventral hernia repair. DESIGN: Retrospective medical record review of an accumulated database. SETTING: University tertiary care medical center. PATIENTS: All patients who underwent open incisional ventral hernia repair from March 1, 2003, through February 28, 2008. INTERVENTION: Open incisional ventral hernia repair. MAIN OUTCOME MEASURES: Postoperative complications, including hernia recurrences. RESULTS: A total of 507 cases (465 patients; female to male ratio, 1.1:1) met our criteria; median follow-up was 40 months. In 23.5% of the cases, repair had been attempted previously, and 16.4% had previously undergone organ transplant. The postoperative complication rate was 38.1%. Hernias recurred in 18.9% of cases. Perioperative mortality was 1.0%. Patients undergoing transplant were more likely than those not undergoing transplant to have a hernia recurrence (16.3% vs 32.5%; P < .001) and were equally likely to have a postoperative complication (36.9% vs 44.6%; P = .19). Patients who underwent repair of a recurrent incisional hernia were as likely to have a hernia recurrence as those who underwent initial repair (21.0% vs 18.3%; P = .52) but more likely to have an overall complication (47.9% vs 35.1%; P = .01). CONCLUSIONS: In this series of incisional hernia repairs at a tertiary care center, the overall recurrence rate of 18.9% is comparable to that of other published series. Ours is the largest published series of recurrent hernias that shows a recurrence rate comparable to that for initial repairs. This outcome may be the result of greater use of more complex repair techniques.

HOXA3 modulates injury-induced mobilization and recruitment of bone marrow-derived cells.

The regulated recruitment and differentiation of multipotent bone marrow-derived cells (BMDCs) to sites of injury are critical for efficient wound healing. Previously we demonstrated that sustained expression of HOXA3 both accelerated wound healing and promoted angiogenesis in diabetic mice. In this study, we have used green fluorescent protein-positive bone marrow chimeras to investigate the effect of HOXA3 expression on recruitment of BMDCs to wounds. We hypothesized that the enhanced neovascularization induced by HOXA3 is due to enhanced mobilization, recruitment, and/or differentiation of BMDCs. Here we show that diabetic mice treated with HOXA3 displayed a significant increase in both mobilization and recruitment of endothelial progenitor cells compared with control mice. Importantly, we also found that HOXA3-treated mice had significantly fewer inflammatory cells recruited to the wound compared with control mice. Microarray analyses of HOXA3-treated wounds revealed that indeed HOXA3 locally increased expression of genes that selectively promote stem/progenitor cell mobilization and recruitment while also suppressing expression of numerous members of the proinflammatory nuclear factor kappaB pathway, including myeloid differentiation primary response gene 88 and toll-interacting protein. Thus HOXA3 accelerates wound repair by mobilizing endothelial progenitor cells and attenuating the excessive inflammatory response of chronic wounds.

Effects of decreased insulin-like growth factor-1 stimulation on hypoxia inducible factor 1-alpha protein synthesis and function during cutaneous repair in diabetic mice.

Insulin-like growth factor-1 (Igf-1), a critical mediator of tissue repair, is significantly decreased in diabetic wounds. Furthermore, decreased levels of hypoxia-inducible factor 1-alpha (Hif-1alpha) and its target genes are also associated with impaired wound healing in diabetic mice. The aim of our study was to examine whether the reduced levels of Igf-1 are responsible for the reduction in Hif-1alpha protein synthesis and activity in diabetic wounds. We provide evidence that Igf-1 regulates Hif-1alpha protein synthesis and activity during wound repair. In addition, Igf-1 stimulated phosphytidylinositol 3-kinase activity in diabetic fibroblasts, which, in turn, increased activation of the translational regulatory protein, p70 S6 kinase. Moreover, improved healing of diabetic wounds by addition of recombinant IGF-1 protein was associated with an increase in Hif-1alpha protein synthesis and function in vivo.