Mechano-sensitivity of ß2-adrenoceptors enhances constitutive activation of cAMP generation that is inhibited by inverse agonists.

The concept of agonist-independent signalling that can be attenuated by inverse agonists is a fundamental element of the cubic ternary complex model of G protein-coupled receptor (GPCR) activation. This model shows how a GPCR can exist in two conformational states in the absence of ligands; an inactive R state and an active R* state that differ in their affinities for agonists, inverse agonists, and G-protein alpha subunits. The proportion of R* receptors that exist in the absence of agonists determines the level of constitutive receptor activity. In this study we demonstrate that mechanical stimulation can induce ß2-adrenoceptor agonist-independent Gs-mediated cAMP signalling that is sensitive to inhibition by inverse agonists such as ICI-118551 and propranolol. The size of the mechano-sensitive response is dependent on the cell surface receptor expression level in HEK293G cells, is still observed in a ligand-binding deficient D113A mutant ß2-adrenoceptor and can be attenuated by site-directed mutagenesis of the extracellular N-glycosylation sites on the N-terminus and second extracellular loop of the ß2-adrenoceptor. Similar mechano-sensitive agonist-independent responses are observed in HEK293G cells overexpressing the A2A-adenosine receptor. These data provide new insights into how agonist-independent constitutive receptor activity can be enhanced by mechanical stimulation and regulated by inverse agonists.

CXCL17 is an allosteric inhibitor of CXCR4 through a mechanism of action involving glycosaminoglycans.

CXCL17 is a chemokine principally expressed by mucosal tissues, where it facilitates chemotaxis of monocytes, dendritic cells, and macrophages and has antimicrobial properties. CXCL17 is also implicated in the pathology of inflammatory disorders and progression of several cancers, and its expression is increased during viral infections of the lung. However, the exact role of CXCL17 in health and disease requires further investigation, and there is a need for confirmed molecular targets mediating CXCL17 functional responses. Using a range of bioluminescence resonance energy transfer (BRET)-based assays, here we demonstrated that CXCL17 inhibited CXCR4-mediated signaling and ligand binding. Moreover, CXCL17 interacted with neuropillin-1, a VEGFR2 coreceptor. In addition, we found that CXCL17 only inhibited CXCR4 ligand binding in intact cells and demonstrated that this effect was mimicked by known glycosaminoglycan binders, surfen and protamine sulfate. Disruption of putative GAG binding domains in CXCL17 prevented CXCR4 binding. This indicated that CXCL17 inhibited CXCR4 by a mechanism of action that potentially required the presence of a glycosaminoglycan-containing accessory protein. Together, our results revealed that CXCL17 is an endogenous inhibitor of CXCR4 and represents the next step in our understanding of the function of CXCL17 and regulation of CXCR4 signaling.

Association of the FGF4L2 retrogene with fibrocartilaginous embolic myelopathy in dogs.

BACKGROUND: Fibrocartilaginous embolic myelopathy (FCE) is a well-documented condition in dogs although rarely reported in chondrodystrophic breeds. Genetic associations have not been defined. OBJECTIVES: Define the association of the chondrodystrophy-associated FGF4L2 retrogene with histopathologically confirmed cases of FCE. ANIMALS: Ninety-eight dogs with a histopathologic diagnosis of FCE. METHODS: Retrospective multicenter study. Dogs were genotyped for the FGF4L2 and FGF4L1 retrogenes using DNA extracted from formalin-fixed, paraffin-embedded tissue. Associations between breed, FCE and retrogene status were investigated with reference to a hospital population and known breed and general population allele frequencies. RESULTS: FGF4L2 genotype was defined in 89 FCE cases. Fibrocartilaginous embolic myelopathy was present in 22 dogs from FGF4L2-segregating breeds with allele frequencies of ≥5%; however, all dogs were wild type. Two Labrador retrievers with FCE carried FGF4L2 alleles. Frequency of the FGF4L2 allele was significantly (P < .001) and negatively associated with FCE relative to predicted hospital-population dogs. FCE was overrepresented in Boxer, Great Dane, Yorkshire Terrier, Bernese Mountain Dog, Miniature Schnauzer, Rottweiler, and Shetland Sheepdog breeds. CONCLUSIONS AND CLINICAL IMPORTANCE: Study data based on genotypically and histopathologically defined cases support the historical observation that FCE is uncommon in chondrodystrophic dog breeds. FGF4 plays an important role in angiogenesis and vascular integrity; anatomical studies comparing chondrodystrophic and non-chondrodystrophic dogs might provide insight into the pathogenesis of FCE.

Should We Fix the Fibula in Tibial Plafond Fractures? A Meta-analysis Reviewing the Evidence Base for Fibula Open Reduction and Internal Fixation in Tibial Plafond Fractures.

Open reduction and internal fixation are the standard of care to stabilize tibial plafond fractures. However, it remains uncertain as to whether fixation of the fibula affects the outcome. This study aimed to review the evidence base for comparable outcomes in tibial plafond fractures when undergoing open reduction and internal fixation of ipsilateral fibula fractures compared with open reduction and internal fixation of the tibia alone. A systematic review and meta-analysis of the literature was completed; 4 studies were included for analysis. This study demonstrated no statistically significant differences in the incidence of nonunion (p = .784) or mal-union (p = .416). There was a greater rate of removal of metalwork in the fibula operative group compared to the tibia alone group (p < .001). The current evidence demonstrates that open reduction and internal fixation of ipsilateral fibula fractures in tibial plafond fractures is not necessarily routinely indicated for all fractures.

Glioma with cribriform plate involvement in 6 dogs.

Distinct patterns of local infiltration are a common feature of canine oligodendroglioma and astrocytoma, and typically involve the surrounding neuroparenchyma, ventricles, or leptomeninges. Infiltration of adjacent extraneural sites is rare and has not been well documented in veterinary medicine. Here we describe 6 canine gliomas with cribriform plate involvement (compression or infiltration) and caudal nasal invasion confirmed by neuroimaging, autopsy, and/or histology. All affected dogs were adults (9-12-y-old), and 3 were brachycephalic. Clinical signs were associated with the brain tumor, with no respiratory signs reported. Magnetic resonance imaging in 2 patients revealed a rostral intraparenchymal telencephalic mass with extension into the cribriform plate. All dogs were euthanized. Gross changes consisted of poorly demarcated, white or pale-yellow, soft, and, in oligodendrogliomas, gelatinous, intraparenchymal masses that expanded the rostral portions of the telencephalon and adhered firmly to the ethmoid bone and cribriform plate. Gliomas were classified as high-grade oligodendrogliomas (4 cases) and high-grade astrocytomas (2 cases) based on histology and immunohistochemistry for OLIG2 and GFAP. In all cases, there was evidence of cribriform plate invasion and, in one case, additional invasion of the caudal nasal cavity.

Case report: Surgical treatment and long-term successful outcome of a spinal intramedullary vascular malformation in a dog.

A 3.5-year-old male intact Staffordshire terrier crossbreed dog was presented with a one-week history of progressive paraparesis with fecal and urinary incontinence. Neurological examination was consistent with a T3-L3 myelopathy. A magnetic resonance imaging study revealed the presence of a well-circumscribed hemorrhagic space-occupying lesion at the level of T12, suspected to be a vascular malformation, such as cavernoma or arteriovenous fistula, primary hematoma or hamartoma; less likely considerations included hemorrhagic inflammation or hemorrhagic primary or secondary neoplasia. A dorsal laminectomy, durotomy, and midline dorsal myelotomy were performed with a surgical microscope, and the vascular lesion was identified and removed. Histological examination of surgical samples yielded fibrin, hemorrhage, hematoidin pigment, and some neural tissue. Although a lining wall was visualized during surgery consistent with a vascular malformation, there was no histological confirmation of such a structure, hampering definitive classification of the lesion. There was no gross or histopathological evidence that would support a diagnosis of a hamartoma or benign neoplasia. The dog was paraplegic with intact nociception the day following surgery. Ambulation was recovered within 2 weeks. Progressive and complete recovery of neurological function was seen over the next 12 weeks. No recurrence of neurological dysfunction was seen over a 12-month follow-up period. Surgical treatment should be considered in dogs with spinal intramedullary vascular lesions which can have a successful long-term outcome.

Tanshinone IIA-loaded nanoparticles and neural stem cell combination therapy improves gut homeostasis and recovery in a pig ischemic stroke model.

Impaired gut homeostasis is associated with stroke often presenting with leaky gut syndrome and increased gut, brain, and systemic inflammation that further exacerbates brain damage. We previously reported that intracisternal administration of Tanshinone IIA-loaded nanoparticles (Tan IIA-NPs) and transplantation of induced pluripotent stem cell-derived neural stem cells (iNSCs) led to enhanced neuroprotective and regenerative activity and improved recovery in a pig stroke model. We hypothesized that Tan IIA-NP + iNSC combination therapy-mediated stroke recovery may also have an impact on gut inflammation and integrity in the stroke pigs. Ischemic stroke was induced, and male Yucatan pigs received PBS + PBS (Control, n = 6) or Tan IIA-NP + iNSC (Treatment, n = 6) treatment. The Tan IIA-NP + iNSC treatment reduced expression of jejunal TNF-α, TNF-α receptor1, and phosphorylated IkBα while increasing the expression of jejunal occludin, claudin1, and ZO-1 at 12 weeks post-treatment (PT). Treated pigs had higher fecal short-chain fatty acid (SCFAs) levels than their counterparts throughout the study period, and fecal SCFAs levels were negatively correlated with jejunal inflammation. Interestingly, fecal SCFAs levels were also negatively correlated with brain lesion volume and midline shift at 12 weeks PT. Collectively, the anti-inflammatory and neuroregenerative treatment resulted in increased SCFAs levels, tight junction protein expression, and decreased inflammation in the gut.

"I'd never have that operation again" - a mixed-methods study on how patients react to adverse outcomes following foot and ankle surgery.

BACKGROUND: Adverse outcomes arising from foot and ankle surgery, including lack of pain relief, increased disability and perioperative complications are infrequent but inevitable. This mixed-methods study aims to explore the impact of adverse outcomes on patients following nonemergent foot and ankle surgery. METHODS: Patients who underwent foot and ankle surgery over a two-year period were invited to participate in this study if they reported an adverse outcome. Qualitative assessment consisted of individual semi-structured interviews, designed to explore the decision they made to have surgery and the impact of the outcome after surgery. Quantitative assessment was performed using questionnaires on demographics, current analgesia, foot pain, health-related quality of life, psychological health, and regret. RESULTS: Twelve participants (eight women) consented for inclusion in this study. Current foot pain was high in 10 participants, five met the criteria for central sensitisation syndrome and two had clinically significant pain catastrophising. Most participants regretted their decision to have surgery. The three major themes identified were expectations, communication, and alternatives. CONCLUSIONS: Self-reported adverse outcomes following foot and ankle surgery were prevalent and participants in this study consistently complained of persistent pain. Regret was common and reasons cited for their adverse outcomes centred around the feelings of inadequate communication and failure to meet expectations.

Advancements in drug delivery methods for the treatment of brain disease.

The blood-brain barrier (BBB) presents a formidable obstacle to the effective delivery of systemically administered pharmacological agents to the brain, with ~5% of candidate drugs capable of effectively penetrating the BBB. A variety of biomaterials and therapeutic delivery devices have recently been developed that facilitate drug delivery to the brain. These technologies have addressed many of the limitations imposed by the BBB by: (1) designing or modifying the physiochemical properties of therapeutic compounds to allow for transport across the BBB; (2) bypassing the BBB by administration of drugs via alternative routes; and (3) transiently disrupting the BBB (BBBD) using biophysical therapies. Here we specifically review colloidal drug carrier delivery systems, intranasal, intrathecal, and direct interstitial drug delivery methods, focused ultrasound BBBD, and pulsed electrical field induced BBBD, as well as the key features of BBB structure and function that are the mechanistic targets of these approaches. Each of these drug delivery technologies are illustrated in the context of their potential clinical applications and limitations in companion animals with naturally occurring intracranial diseases.

A Systematic Review of Randomized Controlled Trials in Anterior Cruciate Ligament Reconstruction: Standard Techniques Are Comparable (299 Trials With 25,816 Patients).

PURPOSE: To provide an overview of all published randomized controlled trials (RCTs) in anterior cruciate ligament reconstruction (ACLR) summarizing the available evidence. METHODS: Following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, we searched the Cochrane FIGCentral Register of Controlled Trials, Ovid MEDLINE, and Embase for RCTs of ACLR from their inception to August 26, 2020. Outcome measure was whether RCTs reported statistically significant findings. RCTs were then classified according to their intervention groups in a narrative synthesis of the evidence. RESULTS: In total, 299 RCTs met the inclusion criteria and were included with a total number of 25,186 patients. Only 30 RCTs (10%) reported significant differences between the intervention and the control groups. These included 101 RCTs on grafts, 20 RCTs on tunnel placements, 48 RCTs on graft fixation, 42 RCTs on single-bundle compared with double-bundle reconstructions, 11 RCTs on additional procedures, 11 RCTs on graft tensioning, 5 RCTs on timing of surgery, 25 RCTs on technical variations from standard techniques, 6 RCTs on ACL repair, 5 RCTs on navigation, 16 RCTs on perioperative management, and 9 RCTs on other aspects of ACLR. Only 14 RCTs (4.7%) reported outcomes beyond 10 years with greater allograft failures compared with autografts, high incidence of osteoarthritic changes in reconstructed knees (22%-100%), with no significant differences in outcomes between bioabsorbable or metal screws for graft fixation, patellar versus hamstrings or single- versus double-bundle reconstructions. CONCLUSIONS: The evidence indicates that a standard arthroscopic single- or double-bundle ACLR with hamstrings/patella autografts, transportal technique, and fixation techniques familiar to the surgeon leads to comparable results. This evidence offers surgeons the flexibility to use standard and cost-effective techniques and achieve comparable outcomes. LEVEL OF EVIDENCE: Level II; systematic review of Level I-II randomized controlled trials.

Intracisternal administration of tanshinone IIA-loaded nanoparticles leads to reduced tissue injury and functional deficits in a porcine model of ischemic stroke.

BACKGROUND: The absolute number of new stroke patients is annually increasing and there still remains only a few Food and Drug Administration (FDA) approved treatments with significant limitations available to patients. Tanshinone IIA (Tan IIA) is a promising potential therapeutic for ischemic stroke that has shown success in pre-clinical rodent studies but lead to inconsistent efficacy results in human patients. The physical properties of Tan-IIA, including short half-life and low solubility, suggests that Poly (lactic-co-glycolic acid) (PLGA) nanoparticle-assisted delivery may lead to improve bioavailability and therapeutic efficacy. The objective of this study was to develop Tan IIA-loaded nanoparticles (Tan IIA-NPs) and to evaluate their therapeutic effects on cerebral pathological changes and consequent motor function deficits in a pig ischemic stroke model. RESULTS: Tan IIA-NP treated neural stem cells showed a reduction in SOD activity in in vitro assays demonstrating antioxidative effects. Ischemic stroke pigs treated with Tan IIA-NPs showed reduced hemispheric swelling when compared to vehicle only treated pigs (7.85 ± 1.41 vs. 16.83 ± 0.62%), consequent midline shift (MLS) (1.72 ± 0.07 vs. 2.91 ± 0.36 mm), and ischemic lesion volumes (9.54 ± 5.06 vs. 12.01 ± 0.17 cm3) when compared to vehicle-only treated pigs. Treatment also lead to lower reductions in diffusivity (-37.30 ± 3.67 vs. -46.33 ± 0.73%) and white matter integrity (-19.66 ± 5.58 vs. -30.11 ± 1.19%) as well as reduced hemorrhage (0.85 ± 0.15 vs 2.91 ± 0.84 cm3) 24 h post-ischemic stroke. In addition, Tan IIA-NPs led to a reduced percentage of circulating band neutrophils at 12 (7.75 ± 1.93 vs. 14.00 ± 1.73%) and 24 (4.25 ± 0.48 vs 5.75 ± 0.85%) hours post-stroke suggesting a mitigated inflammatory response. Moreover, spatiotemporal gait deficits including cadence, cycle time, step time, swing percent of cycle, stride length, and changes in relative mean pressure were less severe post-stroke in Tan IIA-NP treated pigs relative to control pigs. CONCLUSION: The findings of this proof of concept study strongly suggest that administration of Tan IIA-NPs in the acute phase post-stroke mitigates neural injury likely through limiting free radical formation, thus leading to less severe gait deficits in a translational pig ischemic stroke model. With stroke as one of the leading causes of functional disability in the United States, and gait deficits being a major component, these promising results suggest that acute Tan IIA-NP administration may improve functional outcomes and the quality of life of many future stroke patients.

Defining a Safe Zone for Percutaneous Screw Fixation of Posterior Malleolar Fractures.

Posterior malleolar fractures require fixation to confer stability to the ankle. Although some have suggested that fractures involving less than 25% of the articular surface require no intervention, estimation of malleolar size on plain imaging is inaccurate. Some posterior malleolar fractures may be particularly suitable for posterior-to-anterior percutaneous screw fixation of the posterior malleolus via a posterolateral approach. We hypothesized that there may be a safe zone in the posterolateral ankle, identifiable with reliable anatomic landmarks, that might allow safe percutaneous screw placement for fracture fixation. The study protocol involved Step 1, in which multiple Kirschner wires were used in a single cadaveric specimen to attempt to identify a safe zone entry point in the posterior ankle, and Step 2, in which a single wire was used in each of six additional cadaveric specimens to test the ability to safely replicate the use of that entry point. In Step 1, a safe zone entry point was identified, located immediately lateral to the Achilles tendon and 1 cm above the level of the tip of the medial malleolus, when visualizing the posterior ankle. In Step 2, using these landmarks and an image intensifier, single wires were then successfully placed in the other six specimens without injury to any significant structure. If confirmed in clinical studies, the safe zone entry point that we have identified could potentially be used to facilitate posterior-to-anterior percutaneous fixation in patients with posterior malleolar fractures for whom open reduction may not be required or may be contraindicated.

A Bibliometric Analysis of 4 Major Foot and Ankle Surgery Journals.

Research publication is a central to the scientific process and comprehensive bibliometric analysis is a leading way to better understand trends within research. Currently, there are limited bibliometric analyses of literature pertaining to foot and ankle surgery. This study aims to quantify the volume of research and investigate what may affect publication and citation. Journals associated with the 3 major orthopedic foot and ankle societies (Foot & Ankle International[FAI], Foot and Ankle Surgery, and The Foot) and one podiatric college (Journal of Foot and Ankle Surgery®) were evaluated from January 2009 to December 2018 using Scopus (Elsevier, Amsterdam, the Netherlands). Descriptive statistics were used to summarize article characteristics and regression modeling was used to determine factors associated with a country's current and future productivity and an article's citation rate. A total of 4994 articles were published over the 10-year period, with the largest contributor of publications being the United States of America (USA), who produced 2096 (41.8%) publications. Regression analysis found no association between a country's productivity and gross domestic product or population. There was no significant relationship between a country's baseline publication rate and future publication rate. The variables significantly associated with an increased citation count were; the number of years since publication, the number of authors, publication in FAI and if the article was a review. To our knowledge this is the largest bibliometric analysis of foot and ankle publications. The majority of research is being produced by the USA, but there are numerous complex factors associated with citation and publication rates. Further research is required to fully assess these factors and characterize the state of foot and ankle surgery research.

Safety and interim survival data after intracranial administration of M032, a genetically engineered oncolytic HSV-1 expressing IL-12, in pet dogs with sporadic gliomas.

OBJECTIVE: The diagnosis of glioma remains disheartening in the clinical realm. While a multitude of studies and trials have shown promise, improvements in overall survival have been disappointing. Modeling these tumors in the laboratory setting has become increasingly challenging, given their complex in situ behavior and interactions for therapeutic evasion. Dogs, particularly brachycephalic breeds, are known to spontaneously develop gliomas that resemble human gliomas both clinically and pathophysiologically, making canines with sporadic tumors promising candidates for study. Typically, survival among these dogs is approximately 2 months with palliation alone. METHODS: The authors have completed the first stage of a unique phase I dose-escalating canine clinical trial in which the safety and tolerability of M032, a nonneurovirulent oncolytic herpes simplex virus-1 vector genetically engineered to express interleukin-12, are being studied in pet dogs with gliomas undergoing maximum safe tumor resection and inoculation of the cavity with the viral infusate. RESULTS: Twenty-five canine patients were enrolled between January 2018 and August 2020. One patient was electively withdrawn from the trial by its owner, and 3 did not receive the virus. For the 21 dogs that remained, 13 had high-grade gliomas, 5 had low-grade gliomas, and 3 were undetermined. According to histopathological analysis, 62% of the tumors were oligodendrogliomas. At the time of this report, the median overall survival from the date of treatment was 151 days (± 78 days). No significant adverse events attributable to M032 or dose-limiting toxicities have been observed to date. CONCLUSIONS: In this largest study of oncolytic viral therapy for canine brain tumors to date, treatment with M032 did not cause harm and the combination of surgery and oncolytic viral therapy may have contributed to prolonged survival in pet dogs with spontaneous gliomas. Forthcoming in-depth radiographic, immunohistochemical, and genetic analyses will afford a more advanced understanding of how this treatment impacts these tumors and the immune system. Our goal is to utilize these findings bitranslationally to inform human studies and refine therapies that will improve outcomes in both humans and pet dogs with gliomas.

Overview of randomised controlled trials in hallux valgus surgery (2,184 patients).

BACKGROUND: The aim of this study is to provide an overview of randomised controlled trials (RCTs) in hallux valgus correction surgery summarising the available high-quality evidence. METHODS: Following PRISMA guidelines, we searched the Cochrane Central Register of Controlled Trials, Ovid MEDLINE (1946 to 1 February 2020) and Embase (1980 to 1 February 2020). We excluded non-randomised trials, systematic reviews and case-series. We also excluded trials of MTPJ arthrodesis. Trials that met our inclusion criteria were assessed by two authors using a binary outcome measure of whether they reported statistically significant findings. These were then classified according to intervention groups. RESULTS: 32 RCTs met the inclusion criteria and were included. The total number of patients in those trials was 2,184. Only 4 RCTs (12.5%) reported significant differences between the intervention and the control groups. The remaining trials evaluated scarf or chevron osteotomies in 18 RCTs, and 10 RCTs compared other osteotomies or technical aspects of hallux valgus surgery using functional and radiological outcome measures with none reporting significant differences. CONCLUSION: Evidence from RCTs of hallux valgus surgery suggest that scarf and chevron osteotomies are the most popular techniques and lead to similar clinical outcomes.

Morphological analysis of Gissane's angle utilising a statistical shape model of the calcaneus.

INTRODUCTION: Gissane's crucial angle (GA) facilitates to diagnose calcaneal fractures, and serves as an indicator of the quality of anatomical reduction after fixation. The study aimed to utilise statistical shape models (SSM) for analysing the complex 3D surface anatomy of the calcaneus represented by the simplified GA measurement on lateral radiographs. MATERIALS AND METHODS: SSMs were generated from CT scans of paired adult calcanei from 10 Japanese and 31 Thai specimens. GA measurements in 3D and 2D were obtained for the lateral, central and medial anatomy of the posterior facet and sinus tarsi. The correlation between calcaneal length and GA was analysed. Regression and principal component (PC) analyses were conducted for analysing morphological variability in calcaneal shape relating to GA. The bilateral symmetry of the obtained measurements was analysed. RESULTS: The mean GA (lateral) for the Japanese specimens was 105.1° ± 7.5 and 105.4° ± 8.5 for the Thai. The projected 2D angles of the central and medial measurements were larger (P < 0.00) than the 3D values. The medial projected 2D angles were larger (P ≤ 0.02) compared to the lateral. Despite the bilateral symmetry of GA and calcaneal length, their correlation displayed clear signs of asymmetry, which was confirmed by regression and PC analyses. CONCLUSIONS: Japanese and Thai specimens revealed lower GAs (both range and mean) compared to reported reference values of other ethnicities. As a reduced GA is generally indicative of a calcaneal fracture, our results are important to surgeons for their diagnostic assessment of Japanese and Thai patients. The results indicate that the GA measurement on a plain radiograph is a simplified representation of the lateral-to-central 3D calcaneal anatomy but significantly underestimates the angle measurement on the medial aspects of the respective surface areas.

Treatment of hallux valgus by Scarf osteotomy - rates and reasons for recurrence and rates of avascular necrosis: A systematic review.

BACKGROUND: We reviewed the rates of and reasons for hallux valgus (HV) recurrence and the rates of avascular necrosis following Scarf osteotomy. METHODS: We searched the Cochrane Library, PubMed, and Embase databases for studies reporting operative management of HV using Scarf osteotomy. The primary endpoints were reasons for and rates of HV recurrence. The secondary endpoint was the rate of avascular necrosis. RESULTS: We included 15 studies with 946 operations for HV. Seven studies reported no recurrence, six reported recurrence rates of 3.6-11.3%, one reported a recurrence rate of 30%, and one reported a recurrence rate of 78%. Thirteen studies (678 feet) reported other complications from Scarf osteotomy without avascular necrosis. CONCLUSIONS: Although HV recurrence is not uncommon following Scarf osteotomy, patient-related factors, surgical competence, and longer follow-up are more likely to be associated with recurrence. Avascular necrosis is an infrequent complication in HV patients treated using Scarf osteotomy.

Dynamic Changes in the Gut Microbiome at the Acute Stage of Ischemic Stroke in a Pig Model.

Stroke is a major cause of death and long-term disability affecting seven million adults in the United States each year. Recently, it has been demonstrated that neurological diseases, associated pathology, and susceptibility changes correlated with changes in the gut microbiota. However, changes in the microbial community in stroke has not been well characterized. The acute stage of stroke is a critical period for assessing injury severity, therapeutic intervention, and clinical prognosis. We investigated the changes in the gut microbiota composition and diversity using a middle cerebral artery (MCA) occlusion ischemic stroke pig model. Ischemic stroke was induced by cauterization of the MCA in pigs. Blood samples were collected prestroke and 4 h, 12 h, 1 day, and 5 days poststroke to evaluate circulating proinflammatory cytokines. Fecal samples were collected prestroke and 1, 3, and 5 days poststroke to assess gut microbiome changes. Results showed elevated systemic inflammation with increased plasma levels of tumor necrosis factor alpha at 4 h and interleukin-6 at 12 h poststroke, relative to prestroke. Microbial diversity and evenness were reduced at 1 day poststroke compared to prestroke. Microbial diversity at 3 days poststroke was negatively correlated with lesion volume. Moreover, beta-diversity analysis revealed trending overall differences over time, with the most significant changes in microbial patterns observed between prestroke and 3 days poststroke. Abundance of the Proteobacteria was significantly increased, while Firmicutes decreased at 3 days poststroke, compared to prestroke populations. Abundance of the lactic acid bacteria Lactobacillus was reduced at 3 days poststroke. By day 5, the microbial pattern returned to similar values as prestroke, suggesting the plasticity of gut microbiome in an acute period of stroke in a pig model. These findings provide a basis for characterizing gut microbial changes during the acute stage of stroke, which can be used to assess stroke pathology and the potential development of therapeutic targets.

The One Health Consortium: Design of a Phase I Clinical Trial to Evaluate M032, a Genetically Engineered HSV-1 Expressing IL-12, in Combination With a Checkpoint Inhibitor in Canine Patients With Sporadic High Grade Gliomas.

As the most common and deadly of primary brain tumors, malignant gliomas have earned their place within one of the most multifaceted and heavily-funded realms of medical research. Numerous avenues of pre-clinical investigation continue to provide valuable insight, but modeling the complex evolution and behavior of these tumors within a host under simulated circumstances may pose challenges to extrapolation of data. Remarkably, certain breeds of pet dogs spontaneously and sporadically develop high grade gliomas that follow similar incidence, treatment, and outcome patterns as their human glioma counterparts. The most malignant of these tumors have been refractory to limited treatment options despite aggressive treatment; outcomes are dismal with median survivals of just over 1 year in humans and 2 months in dogs. Novel treatments are greatly needed and combination therapies appear to hold promise. This clinical protocol, a dose-escalating phase I study in dogs with sporadic malignant glioma, represents a first in comparative oncology and combination immunotherapy. The trial will evaluate M032, an Interleukin-12 expressing Herpes Simplex virus, alone and combined with a checkpoint inhibitor, Indoximod. Extensive pre-clinical work has demonstrated safety of intracranial M032 administration in mice and non-human primates. M032 is currently being tested in humans with high-grade malignant gliomas. Thus, in a novel fashion, both canine and human trials will proceed concurrently allowing a direct "head-to-head" comparison of safety and efficacy. We expect this viral oncolytic therapy to be as safe as it is in human patients and M032 to (a) infect and kill glioma cells, producing a virus and tumor cell antigen-rich debris field; (b) provide an adjuvant effect due to liberation of viral DNA, which is rich in unmethylated CpG sequences that "toggle" TLR-9 receptors; and (c) express IL-12 locally, stimulating induction of TH1 lymphocytes. The resultant immune-mediated anti-viral responses should, through cross-epitope spreading, translate into a strong response to tumor antigens. The ability to compare human and dog responses in real time affords the most stringent test of suitability of the dog as an informative model of human brain tumors. Subsequent studies will allow canine trials to properly inform the design of human trials.

Readability of foot and ankle consent forms in Queensland.

BACKGROUND: The aim of this study was to conduct a readability analysis on both patient take-home information and consent forms for common foot and ankle procedures. Our hypothesis was that the objective reading skills required to read and comprehend the documentation currently in use would exceed the recommendations in place by both national and international bodies. METHODS: The current Queensland Health consent forms are divided into specific subsections. The readability of consent form subsections C and G (sections containing detailed information on risks of the procedure and pertaining to informed patient consent specifically) and patient take-home information (provided as take-home leaflet from the consent form which is procedure specific) was assessed by an online readability software program using five validated methods calculated by application of the algorithms for (i) Flesch-Kincaid grade level, (ii) the SMOG (Simple Measure of Gobbledygook), (iii) Coleman-Liau index, (iv) automated readability index and the (v) Linsear Wriste formula. RESULTS: The mean ± standard deviation reading grade level of risk (section C), grade level of patient consent (section G) and grade level for procedure-specific take-home patient information were 8.7 ± 0.9, 11.6 ± 1.2 and 7.5 ± 0.2, respectively. CONCLUSION: The readability of sections C and G of the Queensland Health consent form exceeds the recommendations by national and international bodies, but the patient take-home information appears suitable. Consideration should be given to lower the reading grade level of patient consent forms to better reflect the reading grade of the Australian population.