Orthopedic postoperative infection profile and antibiotic sensitivity of 2038 patients across 24 countries - Call for region and institution specific surgical antimicrobial prophylaxis.

Purpose: Improper utilization of surgical antimicrobial prophylaxis frequently leads to increased risks of morbidity and mortality.This study aims to understand the common causative organism of postoperative orthopedic infection and document the surgical antimicrobial prophylaxis protocol across various institutions in to order to strengthen surgical antimicrobial prophylaxis practice and provide higher-quality surgical care. Methods: This multicentric multinational retrospective study, includes 24 countries from five different regions (Asia Pacific, South Eastern Africa, Western Africa, Latin America, and Middle East). Patients who developed orthopedic surgical site infection between January 2021 and December 2022 were included. Demographic details, bacterial profile of surgical site infection, and antibiotic sensitivity pattern were documented. Results: 2038 patients from 24 countries were included. Among them 69.7 % were male patients and 64.1 % were between 20 and 60 years. 70.3 % patients underwent trauma surgery and instrumentation was used in 93.5 %. Ceftriaxone was the most common preferred in 53.4 %. Early SSI was seen in 55.2 % and deep SSI in 59.7 %. Western Africa (76 %) and Asia-Pacific (52.8 %) reported a higher number of gram-negative infections whereas gram-positive organisms were predominant in other regions. Most common gram positive organism was Staphylococcus aureus (35 %) and gram-negative was Klebsiella (17.2 %). Majority of the organisms showed variable sensitivity to broad-spectrum antibiotics. Conclusion: Our study strongly proves that every institution has to analyse their surgical site infection microbiological profile and antibiotic sensitivity of the organisms and plan their surgical antimicrobial prophylaxis accordingly. This will help to decrease the rate of surgical site infection, prevent the emergence of multidrug resistance and reduce the economic burden of treatment.

Circular External Fixator Removal in the Outpatient Clinic Using Regional Anaesthesia: A Pilot Study of a Novel Approach.

Introduction: External fixator (EF) devices are commonly used in the management of complex skeletal trauma, as well as in elective limb reconstruction surgery for the management of congenital and acquired pathology. The subsequent removal of an EF is commonly performed under general anaesthesia in an operating theatre. This practice is resource-intensive and limits the amount of time available for other surgical cases in the operating theatre. We aimed to assess the use of regional anaesthesia as an alternative method of analgesia to facilitate the EF removal in an outpatient setting. Design and methods: This prospective case series evaluated the first 50 consecutive cases of EF removal in the outpatient clinic between 10/06/22 and 03/02/23. Regional anaesthesia using ultrasound-guided blockade of peripheral nerves was administered using 1% lidocaine due to its rapid onset and short half-life. Patients were assessed for additional analgesia requirements and then were asked to evaluate their experience and perceived pain using the visual analogue scale (VAS). Results: Fifty patients were included in the study. The mean age was 46.8 years (range 21-85 years). About 54% of the patients were male patients (N = 27). Post-procedure, all patients indicated positive satisfaction ratings, each participant responded as either 'satisfied' (N = 6), 'very satisfied' (N = 24) or 'highly satisfied' (N = 20). In addition, 90% of the participants reported that they would opt for this method of EF removal again in future. The VAS for pain immediately following completion of the procedure was low, with a mean score of 0.36 (range 0-4), where a score of 0 = 'No pain', and 10 = 'worst pain possible'. The median score was 0. Conclusion: We present the first description of outpatient EF removal using regional anaesthesia, with a prospective case series of 50 fully conscious patients from whom the EF was removed. This novel technique is likely to be cost-effective, reproducible, and safe. This technique reduces the burden of EF removal from an operating list and also improves the patient's experience when compared with other forms of conscious sedation. By eliminating the use of Entonox and methoxyflurane for sedation and analgesia, this technique also demonstrates a method of improving environmental sustainability. How to cite this article: Williams LM, Stamps G, Peak H, et al. Circular External Fixator Removal in the Outpatient Clinic Using Regional Anaesthesia: A Pilot Study of A Novel Approach. Strategies Trauma Limb Reconstr 2023;18(1):7-11.

Sternal fractures and thoracic injury: an analysis of 288 sternal fractures attending a major trauma centre.

INTRODUCTION: Sternal fractures (SF) are uncommon injuries usually associated with a significant mechanism of injury. Concomitant injury is likely, and a risk of mortality is substantial. AIM: Our aim in this study was to identify the risk factors for mortality in patients who had sustained sternal fractures. METHODS: We conducted a single centre retrospective review of the trust's Trauma Audit and Research Network Database, from May 2014 to July 2021. Our inclusion criteria were any patients who had sustained a sternal fracture. The regions of injury were defined using the Abbreviated Injury Score. Pearson Chi-Squared, Fisher Exact tests and multivariate regression analyses were performed using IBM SPSS. RESULTS: A total of 249 patients were identified to have sustained a SF. There were 19 patients (7.63%) who had died. The most common concomitant injuries with SF were Rib fractures (56%), Lung Contusions (31.15%) and Haemothorax (21.88%). There was a significant increase in age (59.93 vs 70.06, p = .037) and admission troponin (36.34 vs. 100.50, p = .003) in those who died. There was a significantly lower GCS in those who died (10.05 vs. 14.01, p < .001). On multi regression analysis, bilateral rib injury (p = 0.037, OR 1.104) was the only nominal variable which showed significance in mortality. CONCLUSION: Sternal Fractures are uncommon but serious injuries. Our review has identified that bilateral rib injuries, increase in age, low GCS, and high admission troponin in the context of SF, were associated with mortality.

Clinical outcomes, Kadish-INSICA staging and therapeutic targeting of somatostatin receptor 2 in olfactory neuroblastoma.

INTRODUCTION: Olfactory neuroblastoma (ONB) is a rare cancer of the sinonasal region. We provide a comprehensive analysis of this malignancy with molecular and clinical trial data on a subset of our cohort to report on the potential efficacy of somatostatin receptor 2 (SSTR2)-targeting imaging and therapy. METHODS: We conducted a retrospective analysis of 404 primary, locally recurrent, and metastatic olfactory neuroblastoma (ONB) patients from 12 institutions in the United States of America, United Kingdom and Europe. Clinicopathological characteristics and treatment approach were evaluated. SSTR2 expression, SSTR2-targeted imaging and the efficacy of peptide receptor radionuclide therapy [PRRT](177Lu-DOTATATE) were reported in a subset of our cohort (LUTHREE trial; NCT03454763). RESULTS: Dural infiltration at presentation was a significant predictor of overall survival (OS) and disease-free survival (DFS) in primary cases (n = 278). Kadish-Morita staging and Dulguerov T-stage both had limitations regarding their prognostic value. Multivariable survival analysis demonstrated improved outcomes with lower stage and receipt of adjuvant radiotherapy. Prophylactic neck irradiation significantly reduces the rate of nodal recurrence. 82.4% of the cohort were positive for SSTR2; treatment of three metastatic cases with SSTR2-targeted peptide-radionuclide receptor therapy (PRRT) in the LUTHREE trial was well-tolerated and resulted in stable disease (SD). CONCLUSIONS: This study presents pertinent clinical data from the largest dataset, to date, on ONB. We identify key prognostic markers and integrate these into an updated staging system, highlight the importance of adjuvant radiotherapy across all disease stages, the utility of prophylactic neck irradiation and the potential efficacy of targeting SSTR2 to manage disease.

Novel strategy for improved outcomes of extra-corporeal membrane oxygenation as a treatment for refractory post cardiotomy cardiogenic shock in the current era: a refreshing new perspective.

OBJECTIVES: Post-cardiotomy cardiogenic shock is an infrequent but important cause of death following cardiac surgery. Extra-corporeal membrane oxygenation offers the opportunity for temporary cardiovascular support and myocardial rest, with a view to recovery. We examine our results with our recently-implemented management algorithm. METHODS: We report our series of 15 consecutive patients out of 357 patients [4.2%] who required institution of veno-arterial extra-corporeal membrane oxygenation system support as treatment for Post-cardiotomy cardiogenic shock in the current era [January-2017 to January-2020]. RESULTS: The mean age was 64.3 ± 11.6 years (range: 40-82 years); there were 13 males (86.7%). Duration of veno-arterial extra-corporeal membrane oxygenation support was 6.7 ± 1.9 days. Duration of stay on intensive care unit [ICU] was 18.9 ± 17.1 days. Duration of hospital-stay was 28.3 ± 20.8 days. Survival to discharge and at 2.2 ± 0.9 years was 67%. CONCLUSIONS: We have shown clearly that veno-arterial extra-corporeal membrane oxygenation is an important rescue option for patients who develop refractory post-cardiotomy cardiogenic shock, with improved survival of 67% at 2.2 ± 0.9 years in those placed on post-cardiotomy veno-arterial extra corporeal membrane oxygenation support, which is superior to that reported hitherto in literature. We have sought to highlight the successes of post cardiotomy veno-arterial extra corporeal membrane oxygenation support, with improved results, based on careful patient selection, as well as diligent management of these critically-ill patients in the postoperative period, prior to establishment of irreversible end-organ dysfunction. Our strategy has also helped us rationalize and optimize the use of this expensive treatment modality.

Optimization of Benzothiazole and Thiazole Hydrazones as Inhibitors of Schistosome BCL-2.

Limited therapeutic options are available for the treatment of human schistosomiasis caused by the parasitic Schistosoma flatworm. The B cell lymphoma-2 (BCL-2)-regulated apoptotic cell death pathway in schistosomes was recently characterized and shown to share similarities with the intrinsic apoptosis pathway in humans. Here, we exploit structural differences in the human and schistosome BCL-2 (sBCL-2) pro-survival proteins toward a novel treatment strategy for schistosomiasis. The benzothiazole hydrazone scaffold previously employed to target human BCL-XL was repurposed as a starting point to target sBCL-2. We utilized X-ray structural data to inform optimization and then applied a scaffold-hop strategy to identify the 5-carboxamide thiazole hydrazone scaffold (43) with potent sBCL-2 activity (IC50 30 nM). Human BCL-XL potency (IC50 13 nM) was inadvertently preserved during the optimization process. The lead analogues from this study exhibit on-target activity in model fibroblast cell lines dependent on either sBCL-2 or human BCL-XL for survival. Further optimization of the thiazole hydrazone class is required to exhibit activity in schistosomes and enhance the potential of this strategy for treating schistosomiasis.

Uniportal subxiphoid bilateral removal of self-introduced thoracic foreign bodies.

This is a report of a 31-year-old male refugee, who was admitted to Intensive Therapy Unit after being found in severe chest pain after escaping extreme torture from his home country. He was found to have four nails in his thorax. These were removed using a subxiphoid video-assisted thorascopic surgery (VATS) technique. This technique allowed excellent visualization of the right, left and anterior mediastinal part of the chest and therefore preventing damage or injury to surrounding structures. This was particularly useful in a complex case such as this. By avoiding an intercoastal incision and intercostal manipulation, our patient had limited pain post-procedure facilitating an earlier aggressive mobilization program with potential benefit in terms of improved lung expansion, reduction of atelectasis and lung infections. With the right training, the technical challenges of using the technique should be overcome and thus the benefits of subxiphoid VATS will be offered to a larger portion of thoracic surgical patients.

Use of endoscopic vein harvesting (EVH) during coronary artery bypass grafting in United Kingdom: The EVH survey.

OBJECTIVE: Endoscopic vein harvesting (EVH) is growing in popularity and is the method of choice in many centers worldwide as it is associated with lower complication rates compared to the open vein harvesting. The aim of this study was to determine the current use of EVH during coronary artery bypass grafting among cardiac surgeons in United Kingdom and identify the main concerns that limit the use of this technique. METHODS: We developed an online survey with 16 questions about the use of EVH. An invitation to participate was sent to all the adult cardiac surgeons currently in practice in United Kingdom. RESULTS: A total of 139 surgeons (52%) of 267 currently in practice across 48 different hospitals completed the survey. Twenty five percent of responding surgeons always use EVH while 44% use it for <10% cases. Forty eight percent of responders regard EVH as an expensive technique and 90% believe that EVH is associated with fewer leg wound issues. Seventy five percent of responding surgeons will use it for their patients due to no leg wound issues while 25% believe that the concerns about patency of EVH are genuine. CONCLUSION: The majority of UK cardiac surgeons responding to this survey will preferentially consider EVH for obese and diabetic patients and are convinced by its beneficial impact in reducing leg wound complications. However, the reported routine use of EVH is low. Concerns about cost and patency of the endoscopically harvested vein are the possible barriers for universal adoption of EVH in the United Kingdom.

Logistic regression prediction model identify type 2 diabetes mellitus as a prognostic factor for human papillomavirus-16 associated head and neck squamous cell carcinoma.

BACKGROUND: HPV-16-positive HNSCC and HPV-16-negative HNSCC have different clinical factors, representing distinct forms of cancers. The study aimed to identify patient-specific factors for HPV-16-positive HNSCC based on baseline clinical data. METHOD: Factors associated with HPV-16-positive HNSCC were identified using the data from 210 patients diagnosed with HNSCC at University College of London Hospital between January 1, 2003, and April 30, 2015, inclusive. A series of models were developed using logistic regression methods, and the overall model fit was compared using Akaike Information Criterion. Survival analysis was carried with Cox proportional hazards model for survival-time outcomes. The survival time for individual patients was defined as the time from diagnosis of HNSCC to the date of death from any cause. For patients who did not die, they were censored at the end of study on April 30, 2015. RESULTS: Of the 210 patients, 151 (72%) were found to have HPV-16-positive HNSCC. The logistic regression model showed that the prevalence of developing HPV-16-positive HNSCC was 3.79 times higher in patients with Type 2 Diabetes Mellitus (T2DM) (odd ratio [OR], 3.79; 95% CI, 1.70-8.44) than in those without T2DM, and 8.84 times higher in patients with history of primary HNSCC (OR, 8.84; 95% CI, 2.30-33.88) than in those without a history of primary HNSCC. HPV-16-positive HNSCC was also observed more in tonsils (OR, 4.02; 95% CL, 1.56-10.36) and less in non-alcohol drinker's oral cavity (OR, 0.14; 95% CI, 0.03-0.56). Furthermore, individual patients were followed-up for 1 to 13 years (median of 1 year). Patients with HPV-positive HNSCC had a median survival of 5 years (95% CI, 2.6-7.3 years). Among HPV-16-positive HNSCC cohort, T2DM was a risk for poorer prognosis (hazard ratio, 2.57; 95% Cl, 1.09-6.07), and had lower median survival of 3 years (95% CI, 1.8-4.1 years), as compared to 6 years (95% CI, 2.8-9.1 years) in non-T2DM. CONCLUSIONS: Patient-specific factors for HPV-positive HNSCC are T2DM, history of primary HNSCC and tonsillar site. T2DM is associated with poorer prognosis. These findings suggest that it might be beneficial if routine HPV-16 screening is carried out in T2DM patients which can provide better therapeutic and management strategies.

Follow up results of a prospective study to evaluate the impact of FDG-PET on CT-based radiotherapy treatment planning for oesophageal cancer.

BACKGROUND: This prospective study aims to determine the impact of PET/CT on radiotherapy planning and outcomes in patients with oesophageal cancer. METHODS: All patients underwent PET/CT scanning in the radiotherapy treatment position, and received treatment planned using the PET/CT dataset. GTV was defined separately on PET/CT (GTV-PET) and CT (GTV-CT) datasets. A corresponding PTV was generated for each patient. Volumetric and spatial analysis quantified the proportion of FDG-avid disease not included in CT-based volumes. Clinical data was collected to determine locoregional control and overall survival rates. RESULTS: 13 (24.1%) of 57 accrued patients had metastatic disease detected on PET. Median follow up was 4 years. FDG-avid disease would have been excluded from GTV-CT in 29 of 38 patients (76%). In 5 patients, FDG-avid disease would have been completely excluded from the PTV-CT. GTV-CT underestimated the cranial and caudal extent of FDG-avid tumour in 14 (36%) and 10 (26%) patients. 4-Year overall survival and locoregional failure free survival were 37% and 65%. CONCLUSIONS: PET/CT altered the delineation of tumour volumes when compared to CT alone, and should be considered standard for treatment planning. Although clinical outcomes were not improved with PET/CT planning, it did allow the use of smaller radiotherapy volumes.

Titanium cranioplasty in children and adolescents.

Full thickness calvarial defects present considerable challenges to reconstructive surgeons. In paediatric cases, the use of biomaterials as a substrate for cranioplasty rather than autologous bone is controversial. Alloplastic cranioplasty in adults is supported by several large case series however long term outcome of biomaterial use in paediatric cases is limited. Retrospective seven year analysis of departmental database and clinical records identified 22 patients aged under 18 who had undergone 23 custom made titanium cranioplasties by a single surgeon using the same technique. Data including patient demographics, reason for craniectomy and complications experienced following surgery was obtained. The mean age at operation was 12 years 9 months. The mean defect size was 44.3 cm(2). No significant complications related to the cranioplasty were recorded in the early post operative period or during long term review (average follow up 4 years 6 months). No cranioplasty implant required removal. This retrospective case series shows that custom made patient specific titanium cranioplasty is a viable alternative to autologous bone as a reconstructive material in paediatric patients under specific circumstances.

The Missing Link in Epstein-Barr Virus Immune Evasion: the BDLF3 Gene Induces Ubiquitination and Downregulation of Major Histocompatibility Complex Class I (MHC-I) and MHC-II.

UNLABELLED: The ability of Epstein-Barr virus (EBV) to spread and persist in human populations relies on a balance between host immune responses and EBV immune evasion. CD8(+) cells specific for EBV late lytic cycle antigens show poor recognition of target cells compared to immediate early and early antigen-specific CD8(+) cells. This phenomenon is due in part to the early EBV protein BILF1, whose immunosuppressive activity increases with lytic cycle progression. However, published data suggest the existence of a hitherto unidentified immune evasion protein further enhancing protection against late EBV antigen-specific CD8(+) cells. We have now identified the late lytic BDLF3 gene as the missing link accounting for efficient evasion during the late lytic cycle. Interestingly, BDLF3 also contributes to evasion of CD4(+) cell responses to EBV. We report that BDLF3 downregulates expression of surface major histocompatibility complex (MHC) class I and class II molecules in the absence of any effect upon other surface molecules screened, including CD54 (ICAM-1) and CD71 (transferrin receptor). BDLF3 both enhanced internalization of surface MHC molecules and reduced the rate of their appearance at the cell surface. The reduced expression of surface MHC molecules correlated with functional protection against CD8(+) and CD4(+) T cell recognition. The molecular mechanism was identified as BDLF3-induced ubiquitination of MHC molecules and their subsequent downregulation in a proteasome-dependent manner. IMPORTANCE: Immune evasion is a necessary feature of viruses that establish lifelong persistent infections in the face of strong immune responses. EBV is an important human pathogen whose immune evasion mechanisms are only partly understood. Of the EBV immune evasion mechanisms identified to date, none could explain why CD8(+) T cell responses to late lytic cycle genes are so infrequent and, when present, recognize lytically infected target cells so poorly relative to CD8(+) T cells specific for early lytic cycle antigens. The present work identifies an additional immune evasion protein, BDLF3, that is expressed late in the lytic cycle and impairs CD8(+) T cell recognition by targeting cell surface MHC class I molecules for ubiquitination and proteasome-dependent downregulation. Interestingly, BDLF3 also targets MHC class II molecules to impair CD4(+) T cell recognition. BDLF3 is therefore a rare example of a viral protein that impairs both the MHC class I and class II antigen-presenting pathways.

Induction of the Lytic Cycle Sensitizes Epstein-Barr Virus-Infected B Cells to NK Cell Killing That Is Counteracted by Virus-Mediated NK Cell Evasion Mechanisms in the Late Lytic Cycle.

UNLABELLED: Epstein-Barr Virus (EBV) persists for the lifetime of the infected host despite eliciting strong immune responses. This persistence requires a fine balance between the host immune system and EBV immune evasion. Accumulating evidence suggests an important role for natural killer (NK) cells in this balance. NK cells can kill EBV-infected cells undergoing lytic replication in vitro, and studies in both humans and mice with reconstituted human immune systems have shown that NK cells can limit EBV replication and prevent infectious mononucleosis. We now show that NK cells, via NKG2D and DNAM-1 interactions, recognize and kill EBV-infected cells undergoing lytic replication and that expression of a single EBV lytic gene, BZLF1, is sufficient to trigger sensitization to NK cell killing. We also present evidence suggesting the possibility of the existence of an as-yet-unidentified DNAM-1 ligand which may be particularly important for killing lytically infected normal B cells. Furthermore, while cells entering the lytic cycle become sensitized to NK cell killing, we observed that cells in the late lytic cycle are highly resistant. We identified expression of the vBcl-2 protein, BHRF1, as one effective mechanism by which EBV mediates this protection. Thus, contrary to the view expressed in some reports, EBV has evolved the ability to evade NK cell responses. IMPORTANCE: This report extends our understanding of the interaction between EBV and host innate responses. It provides the first evidence that the susceptibility to NK cell lysis of EBV-infected B cells undergoing lytic replication is dependent upon the phase of the lytic cycle. Induction of the lytic cycle is associated with acquired sensitization to NK cell killing, while progress through the late lytic cycle is associated with acquired resistance to killing. We provide mechanistic explanations for this novel observation, indicating important roles for the BZLF1 immediate early transactivator, the BHRF1 vBcl-2 homologue, and a novel ligand for the DNAM-1 NK cell receptor.

Radiotherapy of abdomen with precise renal assessment with SPECT/CT imaging (RAPRASI): design and methodology of a prospective trial to improve the understanding of kidney radiation dose response.

BACKGROUND: The kidneys are a principal dose-limiting organ in radiotherapy for upper abdominal cancers. The current understanding of kidney radiation dose response is rudimentary. More precise dose-volume response models that allow direct correlation of delivered radiation dose with spatio-temporal changes in kidney function may improve radiotherapy treatment planning for upper-abdominal tumours. METHODS/DESIGN: The Radiotherapy of Abdomen with Precise Renal Assessment with SPECT/CT Imaging (RAPRASI) is an observational clinical research study with participating sites at Sir Charles Gairdner Hospital (SCGH) in Perth, Australia and the Peter MacCallum Cancer Centre (PMCC) in Melbourne, Australia. Eligible patients are those with upper gastrointestinal cancer, without metastatic disease, undergoing conformal radiotherapy that will involve incidental radiation to one or both kidneys. For each patient, total kidney function is being assessed before commencement of radiotherapy treatment and then at 4, 12, 26, 52 and 78 weeks after the first radiotherapy fraction, using two procedures: a Glomerular Filtration Rate (GFR) measurement using the 51Cr-ethylenediamine tetra-acetic acid (EDTA) clearance; and a regional kidney perfusion measurement assessing renal uptake of 99mTc-dimercaptosuccinic acid (DMSA), imaged with a Single Photon Emission Computed Tomography / Computed Tomography (SPECT/CT) system. The CT component of the SPECT/CT provides the anatomical reference of the kidney's position. The data is intended to reveal changes in regional kidney function over the study period after the radiotherapy. These SPECT/CT scans, co-registered with the radiotherapy treatment plan, will provide spatial correlation between the radiation dose and regional renal function as assessed by SPECT/CT. From this correlation, renal response patterns will likely be identified with the purpose of developing a predictive model. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry: ACTRN12609000322235.

Computed tomography overestimation of esophageal tumor length: Implications for radiotherapy planning.

AIM: To assess the relationship between preoperative computed tomography (CT) and postoperative pathological measurements of esophageal tumor length and the prognostic significance of CT tumor length data. METHODS: A retrospective study was carried out in 56 patients who underwent curative esophagogastrectomy. Tumor lengths were measured on the immediate preoperative CT and on the post-operative resection specimens. Inter- and intra-observer variations in CT measurements were assessed. Survival data were collected. RESULTS: There was a weak correlation between CT and pathological tumor length (r = 0.30, P = 0.025). CT lengths were longer than pathological lengths in 68% (38/56) of patients with a mean difference of 1.67 cm (95% CI: 1.18-2.97). The mean difference in measurements by two radiologists was 0.39 cm (95% CI: -0.59-1.44). The mean difference between repeat CT measured tumor length (intra-observer variation) were 0.04 cm (95% CI: -0.59-0.66) and 0.47 cm (95% CI: -0.53-1.47). When stratified, patients not receiving neoadjuvant chemotherapy showed a strong correlation between CT and pathological tumor length (r = 0.69, P = 0.0014, n = 37) than patients that did (r = 0.13, P = 0.43, n = 19). Median survival with CT tumor length > 5.6 cm was poorer than with smaller tumors, but the difference was not statistically significant. CONCLUSION: Esophageal tumor length assessed using CT does not reflect pathological tumor extent and should not be the only modality used for management decisions, particularly for planning radiotherapy.

Adverse events associated with anticoagulation therapy in the periendoscopic period.

BACKGROUND: Chronic anticoagulation has been demonstrated to be a risk factor for GI bleeding (GIB) in patients undergoing endoscopic procedures. OBJECTIVE: The aim of this study was to determine the incidence of GIB prospectively in a large cohort of patients enrolled in the Clinical Outcomes Research Initiative (CORI) database. DESIGN: Anticoagulated patients undergoing endoscopic procedures were interviewed by phone 30 to 45 days after the procedure to determine potential adverse events and management of warfarin therapy in the periendoscopic period. SETTING: Participating CORI sites, Stanford University Hospital, Veterans Administration Palo Alto Health Care System. MAIN OUTCOME MEASUREMENT: Postprocedural hemorrhagic or thrombotic events. RESULTS: Thirteen CORI sites agreed to participate, including 120,886 procedures in 95,807 patients. We contacted 929 patients on warfarin therapy and enrolled 483 patients (52%). The majority of the patients were men with atrial fibrillation undergoing colonoscopy. Warfarin was temporarily suspended in 437 (90%) of the patients before the procedure, and 114 (22%) received periprocedural heparin therapy. There were 10 major hemorrhagic events (2%), and the rate of hemorrhage was not higher in the patients receiving periprocedural heparin therapy (P = .1). However, polypectomy was a risk factor for postprocedural hemorrhage (P = .02). One fatal stroke (0.2%) occurred in a patient 2 weeks after endoscopy; however, information regarding warfarin management was not available. LIMITATIONS: Small number of enrolled patients and lack of control group. Lack of information regarding prothrombin time before procedure, concurrent antiplatelet agents, and timing of bleeding in 50% of the cases. The study was underpowered to definitively conclude benefits of current guidelines regarding thrombosis or bleeding. CONCLUSIONS: Postprocedural hemorrhagic events were not increased in anticoagulated patients. Most patients receiving bridging therapy were managed according to current society guidelines.

Retrospective review of donor site complications after harvest of cancellous bone from the anteriomedial tibia.

Donor site morbidity is important in deciding the site for harvest of cancellous bone for alveolar bone grafts. Many studies have supported the view that tibia is safe with few complications in the short term. We know of no studies on the long-term complications to the donor site after tibial bone grafting in children with alveolar clefts. The casenotes of 40 children who had had tibial bone grafts for alveolar clefts were studied retrospectively, and parents or patients were contacted by telephone and a standardised questionnaire was used to assess any long term complications at the donor site. We found none. We found no evidence of long-term complications at the donor site in children who had had proximal tibial bone grafting for secondary repair of alveolar clefts. We conclude that the proximal tibia is a safe site from which to obtain cancellous bone graft for alveolar clefts in children. This study is preliminary, and highlights the need for a randomised trial.

Hyper-IgE syndrome is not associated with defects in several candidate toll-like receptor pathway genes.

The genetic basis of hyper-IgE syndrome (HIES), also known as Job syndrome, a primary immunodeficiency associated with recurrent skin and pulmonary infections, is unknown. We hypothesized that HIES is due to a defect in the Toll-like receptor signaling pathway. We used a whole blood cytokine assay to compare inflammatory responses to stimulation with specific Toll-like receptor (TLR) pathway agonists in four individuals with HIES and nine healthy controls. Production of tumor necrosis factor-alpha, interleukin (IL)-1beta, IL-6, and IL-12 was not impaired in response to stimulation with lipopolysaccharide, peptidoglycan, zymosan, lipoteichoic acid, Staphylococcus aureus, Escherichia coli, or Streptococcus pneumoniae. Interferon (IFN)-gamma was reduced in HIES subjects in response to each of these stimuli. We sequenced several candidate genes from the TLR pathway in HIES individuals to determine whether any mutations were associated with this syndrome. No novel mutations or polymorphisms were found in the coding regions of TLR1, TLR2, TLR6, MyD88, or TRAF6. In summary, although HIES individuals had an IFN-gamma secretion defect, they also produced normal levels of several TLR-regulated proinflammatory cytokines. No unique mutations or polymorphisms were observed in several candidate genes from the TLR pathway. Our studies do not support a role for a defective TLR response in HIES individuals.

Regulatory T cell lineage specification by the forkhead transcription factor foxp3.

Regulatory T cell-mediated dominant tolerance has been demonstrated to play an important role in the prevention of autoimmunity. Here, we present data arguing that the forkhead transcription factor Foxp3 acts as the regulatory T cell lineage specification factor and mediator of the genetic mechanism of dominant tolerance. We show that expression of Foxp3 is highly restricted to the subset alphabeta of T cells and, irrespective of CD25 expression, correlates with suppressor activity. Induction of Foxp3 expression in nonregulatory T cells does not occur during pathogen-driven immune responses, and Foxp3 deficiency does not impact the functional responses of nonregulatory T cells. Furthermore, T cell-specific ablation of Foxp3 is sufficient to induce the identical early onset lymphoproliferative syndrome observed in Foxp3-deficient mice. Analysis of Foxp3 expression during thymic development suggests that this mechanism is not hard-wired but is dependent on TCR/MHC ligand interactions.