Surgical Site Infections after Open Reduction Internal Fixation for Trauma in Low and Middle Human Development Index Countries: A Systematic Review.

BACKGROUND: Musculoskeletal trauma represents a large source of morbidity in low and middle human development index countries (LMHDICs). Open reduction and internal fixation (ORIF) of traumatic long bone fractures definitively manages these injuries and restores function when conducted safely and effectively. Surgical site infections (SSIs) are a common complication of operative fracture fixation, although the risks of infection are ill-defined in LMHDIC. PATIENTS AND METHODS: This study reviewed systematically all studies describing SSI after ORIF in LMDHICs. Studies were reviewed based on their qualitative characteristics, after which a quantitative synthesis of weighted pooled infection rates based on available patient-level data was performed to estimate published incidence of SSI. RESULTS: Forty-two studies met criteria for qualitative review and 32 studies comprising 3,084 operations were included in the quantitative analysis. Among 3,084 operations, the weighted pooled SSI rate was 6.4 infections per 100 procedures (95% confidence interval [CI] 4.6-8.2 infections per 100 procedures). Higher rates of infection were noted among the sub-group of open fractures (95% CI 13.9-23.0 infections per 100 procedures). Lower extremity injuries and procedures utilizing intra-medullary nails also had slightly higher rates of infection versus upper extremity procedures and other fixation devices. CONCLUSIONS: Reported rates of SSI after ORIF are higher in LMHDICs, and may be driven by high rates of infection in the sub-group of open fractures. This study provides a baseline SSI rate obtained from literature produced from LMHDICs. Infection rates are highly dependent on fracture sub-types.

Bilateral Sacral Ala Fractures Are Strongly Associated With Lumbopelvic Instability.

OBJECTIVES: To quantify the incidence of lumbopelvic instability in the setting of unilateral and bilateral sacral fractures and assess whether the presence of bilateral sacral fractures on axial imaging is a useful screening test for lumbopelvic instability. DESIGN: Retrospective case series. SETTING: Level I trauma center at an academic medical center. PATIENTS/PARTICIPANTS: A hospital database was used to identify patients diagnosed with a sacral fracture by The International Classification of Diseases, Ninth Revision (ICD-9) code from 2000 to 2014. INTERVENTION: Axial cross-sectional imaging was reviewed to confirm the presence of unilateral or bilateral sacral ala fractures. Sagittal reconstructions were scrutinized for a transverse fracture line separating the lumbar spine from the pelvis, which was used to define lumbopelvic instability. MAIN OUTCOME MEASUREMENTS: The Roy-Camille classification system was applied to all identified cases of lumbopelvic instability. RESULTS: One thousand five hundred twenty-six patients were diagnosed with sacral fractures by the ICD-9 code. Four hundred ninety had adequate axial and sagittal cross-sectional imaging. Four hundred forty-three of these patients had unilateral sacral ala fractures, and none of these were associated with lumbopelvic instability. Forty-seven patients had bilateral sacral ala fractures, and 41 of these (87%) had a transverse component indicating some degree of lumbopelvic instability. The presence of bilateral sacral fractures was 100% sensitive and 99% specific for lumbopelvic instability. Among fractures with lumbopelvic instability, 27 (66%) were Roy-Camille type 1, 11 (27%) were type 2, and 3 (7%) were type 3. CONCLUSIONS: Bilateral sacral ala fractures are strongly associated with lumbopelvic instability and can be used as a very sensitive and specific screening tool. All patients with bilateral sacral fractures on axial computed tomography or magnetic resonance imaging should have close assessment of the sagittal plane images to evaluate for this pathology. LEVEL OF EVIDENCE: Diagnostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Functional assessment of the acute local and distal transplantation of human neural stem cells after spinal cord injury.

BACKGROUND CONTEXT: Spinal cord injury can lead to severe functional impairments secondary to axonal damage, neuronal loss, and demyelination. The injured spinal cord has limited regrowth of damaged axons. Treatment remains controversial, given inconsistent functional improvement. Previous studies demonstrated functional recovery of rats with spinal cord contusion after transplantation of rat fetal neural stem cells. PURPOSE: We hypothesized that acute transplantation of human fetal neural stem cells (hNSCs) both locally at the injury site as well as distally via intrathecal injection would lead to improved functional recovery compared with controls. STUDY DESIGN/SETTING: Twenty-four adult female Long-Evans hooded rats were randomized into four groups with six animals in each group: two experimental and two control. Functional assessment was measured after injury and then weekly for 6 weeks using the Basso, Beattie, and Bresnahan Locomotor Rating Score. Data were analyzed using two-sample t test and linear mixed-effects model analysis. METHODS: Posterior exposure and laminectomy at T10 level was used. Moderate spinal cord contusion was induced by the Multicenter Animal Spinal Cord Injury Study Impactor with 10-g weight dropped from a height of 25 mm. Experimental subjects received either a subdural injection of hNSCs locally at the injury site or intrathecal injection of hNSCs through a separate distal laminotomy. Controls received control media injection either locally or distally. RESULTS: Statistically significant functional improvement was observed in local or distal hNSCs subjects versus controls (p=.034 and 0.016, respectively). No significant difference was seen between local or distal hNSC subjects (p=.66). CONCLUSIONS: Acute local and distal transplantation of hNSCs into the contused spinal cord led to significant functional recovery in the rat model. No statistical difference was found between the two techniques.

Aberrant epithelial-mesenchymal Hedgehog signaling characterizes Barrett's metaplasia.

BACKGROUND & AIMS: The molecular mechanism underlying epithelial metaplasia in Barrett's esophagus remains unknown. Recognizing that Hedgehog signaling is required for early esophageal development, we sought to determine if the Hedgehog pathway is reactivated in Barrett's esophagus, and if genes downstream of the pathway could promote columnar differentiation of esophageal epithelium. METHODS: Immunohistochemistry, immunofluorescence, and quantitative real-time polymerase chain reaction were used to analyze clinical specimens, human esophageal cell lines, and mouse esophagi. Human esophageal squamous epithelial (HET-1A) and adenocarcinoma (OE33) cells were subjected to acid treatment and used in transfection experiments. Swiss Webster mice were used in a surgical model of bile reflux injury. An in vivo transplant culture system was created using esophageal epithelium from Sonic hedgehog transgenic mice. RESULTS: Marked up-regulation of Hedgehog ligand expression, which can be induced by acid or bile exposure, occurs frequently in Barrett's epithelium and is associated with stromal expression of the Hedgehog target genes PTCH1 and BMP4. BMP4 signaling induces expression of SOX9, an intestinal crypt transcription factor, which is highly expressed in Barrett's epithelium. We further show that expression of Deleted in Malignant Brain Tumors 1, the human homologue of the columnar cell factor Hensin, occurs in Barrett's epithelium and is induced by SOX9. Finally, transgenic expression of Sonic hedgehog in mouse esophageal epithelium induces expression of stromal Bmp4, epithelial Sox9, and columnar cytokeratins. CONCLUSIONS: Epithelial Hedgehog ligand expression may contribute to the initiation of Barrett's esophagus through induction of stromal BMP4, which triggers reprogramming of esophageal epithelium in favor of a columnar phenotype.

Cooperation between the Hic1 and Ptch1 tumor suppressors in medulloblastoma.

Medulloblastoma is an embryonal tumor thought to arise from the granule cell precursors (GCPs) of the cerebellum. PATCHED (PTCH), an inhibitor of Hedgehog signaling, is the best-characterized tumor suppressor in medulloblastoma. However, <20% of medulloblastomas have mutations in PTCH. In the search for other tumor suppressors, interest has focused on the deletion events at the 17p13.3 locus, the most common genetic defect in medulloblastoma. This chromosomal region contains HYPERMETHYLATED IN CANCER 1 (HIC1), a transcriptional repressor that is a frequent target of epigenetic gene silencing in medulloblastoma. Here we use a mouse model of Ptch1 heterozygosity to reveal a critical tumor suppressor function for Hic1 in medulloblastoma. When compared with Ptch1 heterozygous mutants, compound Ptch1/Hic1 heterozygotes display a fourfold increased incidence of medulloblastoma. We show that Hic1 is a direct transcriptional repressor of Atonal Homolog 1 (Atoh1), a proneural transcription factor essential for cerebellar development, and show that ATOH1 expression is required for human medulloblastoma cell growth in vitro. Given that Atoh1 is also a putative target of Hh signaling, we conclude that the Hic1 and Ptch1 tumor suppressors cooperate to silence Atoh1 expression during a critical phase in GCP differentiation in which malignant transformation may lead to medulloblastoma.

Hedgehog signaling maintains a tumor stem cell compartment in multiple myeloma.

The cancer stem cell hypothesis suggests that malignant growth depends on a subset of tumor cells with stem cell-like properties of self-renewal. Because hedgehog (Hh) signaling regulates progenitor cell fate in normal development and homeostasis, aberrant pathway activation might be involved in the maintenance of such a population in cancer. Indeed, mutational activation of the Hh pathway is associated with medulloblastoma and basal cell carcinoma; pathway activity is also critical for growth of other tumors lacking such mutations, although the mechanism of pathway activation is poorly understood. Here we study the role and mechanism of Hh pathway activation in multiple myeloma (MM), a malignancy with a well defined stem cell compartment. In this model, rare malignant progenitors capable of clonal expansion resemble B cells, whereas the much larger tumor cell population manifests a differentiated plasma cell phenotype that pathologically defines the disease. We show that the subset of MM cells that manifests Hh pathway activity is markedly concentrated within the tumor stem cell compartment. The Hh ligand promotes expansion of MM stem cells without differentiation, whereas the Hh pathway blockade, while having little or no effect on malignant plasma cell growth, markedly inhibits clonal expansion accompanied by terminal differentiation of purified MM stem cells. These data reveal that Hh pathway activation is heterogeneous across the spectrum of MM tumor stem cells and their more differentiated progeny. The potential existence of similar relationships in other adult cancers may have important biologic and clinical implications for the study of aberrant Hh signaling.