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The certainty that prehabilitation improves postoperative outcomes is not clear. The objective of this umbrella review (i.e. systematic review of systematic reviews) was to synthesise and evaluate evidence for prehabilitation in improving health, experience, or cost outcomes.We performed an umbrella review of prehabilitation systematic reviews. MEDLINE, Embase, Cochrane, Cumulative Index to Nursing and Allied Health Literature, PsycINFO, Joanna Briggs Institute's database, and Web of Science were searched (inception to October 20, 2020). We included all systematic reviews of elective, adult patients undergoing surgery and exposed to a prehabilitation intervention, where health, experience, or cost outcomes were reported. Evidence certainty was assessed using Grading of Recommendations Assessment, Development and Evaluation. Primary syntheses of any prehabilitation were stratified by surgery type.From 1412 titles, 55 systematic reviews were included. For patients with cancer undergoing surgery who participate in any prehabilitation, moderate certainty evidence supports improvements in functional recovery. Low to very low certainty evidence supports reductions in complications (mixed, cardiovascular, and cancer surgery), non-home discharge (orthopaedic surgery), and length of stay (mixed, cardiovascular, and cancer surgery). There was low to very low certainty evidence that exercise prehabilitation reduces the risk of complications, non-home discharge, and length of stay. There was low to very low certainty evidence that nutritional prehabilitation reduces risk of complications, mortality, and length of stay.Low certainty evidence suggests that prehabilitation may improve postoperative outcomes. Future low risk of bias, randomised trials, synthesised using recommended standards, are required to inform practice. Optimal patient selection, intervention design, and intervention duration must also be determined.

Background Histiocytic sarcoma is a rare disorder in humans, however it is seen with appreciable frequency in certain breeds of dogs, such as Bernese mountain dog. The purpose of this study was to fully characterize a novel canine histiocytic sarcoma cell line, and utilize it as a tool to screen for potential therapeutic drugs. Methods The histiocytic sarcoma cell line was characterized by expression of cellular markers as determined by immunohistochemistry and flow cytometry techniques. The neoplastic cells were also evaluated for their capability of phagocytizing beads particles, and their potential to grow as xenograft in an immunodeficient mouse. We investigated the in vitro cytotoxic activity of a panel of thirteen compounds using the MTS proliferation assay. Inhibitory effects of different drugs were compared using one-way ANOVA, and multiple means were compared using Tukey’s test. Results Neoplastic cells expressed CD11c, CD14, CD18, CD45, CD172a, CD204, MHC I, and vimentin. Expression of MHC II was upregulated after exposure to LPS. Furthermore, the established cell line clearly demonstrated phagocytic activity similar to positive controls of macrophage cell line. The xenograft mouse developed a palpable subcutaneous soft tissue mass after 29 days of inoculation, which histologically resembled the primary neoplasm. Dasatinib, a tyrosine kinase pan-inhibitor, significantly inhibited the growth of the cells in vitro within a clinically achievable and tolerable plasma concentration. The inhibitory response to dasatinib was augmented when combined with doxorubicin. Conclusions In the present study we demonstrated that a novel canine histiocytic sarcoma cell line presents a valuable tool to evaluate novel treatment approaches. The neoplastic cell line favorably responded to dasatinib, which represents a promising anticancer strategy for the treatment of this malignancy in dogs and similar disorders in humans. Electronic supplementary material The online version of this article (10.1186/s12885-018-4132-0) contains supplementary material, which is available to authorized users.

Canine nonangiogenic, nonlymphogenic, gastrointestinal sarcomas have been previously diagnosed as gastrointestinal stromal tumors (GIST), leiomyosarcomas, or nonspecified spindle cell sarcomas, but diagnostic criteria for each entity are poorly defined. We propose a classification for canine nonangiogenic, nonlymphogenic, gastrointestinal sarcomas based on microscopic, immunohistochemical, and molecular characteristics. Applying the classification to 40 canine nonangiogenic, nonlymphogenic, gastrointestinal sarcomas documented its diagnostic and prognostic value. Eighteen (45%) sarcomas were classified as GIST based on positive KIT immunoreactivity. All GISTs were positive for vimentin, 14 (78%) were positive for S-100, and 6 (33%) were positive for smooth muscle actin (SMA). In contrast to their human counterparts, canine GISTs occurred mainly in the small intestine (67%) but commonly metastasized (5/18) to liver, lymph nodes, and omentum. Six GISTs had an activated KIT mutation in exon 11 of c-Kit, but no mutations were detected in exons 8, 9, 13, and 17. Twelve (30%) sarcomas were classified as leiomyosarcomas based on positive labeling for SMA and negative labeling for KIT. Four of these neoplasms were well differentiated leiomyosarcomas characterized by weak to no labeling for vimentin, and 8 were poorly differentiated leiomyosarcomas characterized by strong labeling for vimentin. None of the leiomyosarcomas metastasized, but poorly differentiated leiomyosarcomas had a higher risk of local invasion. Ten (25%) sarcomas were classified as non-GIST/nonleiomyosarcomas that were negative for KIT and SMA but positive for vimentin and either S-100 and/or PGP 9.5. These neoplasms most likely represent sarcomas of neurogenic differentiation resembling Schwann cells or perineurial or endoneurial fibroblasts, respectively.

Cerebral oxygen desaturation during cardiac surgery has been associated with adverse perioperative outcomes. Before a large multicenter randomized controlled trial (RCT) on the impact of preventing desaturations on perioperative outcomes, the authors undertook a randomized prospective, parallel-arm, multicenter feasibility RCT to determine whether an intervention algorithm could prevent desaturations.Eight Canadian sites randomized 201 patients between April 2012 and October 2013. The primary outcome was the success rate of reversing cerebral desaturations below 10% relative to baseline in the intervention group. Anesthesiologists were blinded to the cerebral saturation values in the control group. Intensive care unit personnel were blinded to cerebral saturation values for both groups. Secondary outcomes included the area under the curve of cerebral desaturation load, enrolment rates, and a 30-day follow-up for adverse events.Cerebral desaturations occurred in 71 (70%) of the 102 intervention group patients and 56 (57%) of the 99 control group patients (P = 0.04). Reversal was successful in 69 (97%) of the intervention group patients. The mean cerebral desaturation load (SD) in the operating room was smaller for intervention group patients compared with control group patients (104 [217] %.min vs. 398 [869] %.min, mean difference, -294; 95% CI, -562 to -26; P = 0.03). This was also true in the intensive care unit (P = 0.02). There were no differences in adverse events between the groups.Study sites were successful in reversal of desaturation, patient recruitment, randomization, and follow-up in cardiac surgery, supporting the feasibility of conducting a large multicenter RCT.

SummaryBackgroundTrials of β blockers in patients undergoing non-cardiac surgery have reported conflicting results. This randomised controlled trial, done in 190 hospitals in 23 countries, was designed to investigate the effects of perioperative β blockers.MethodsWe randomly assigned 8351 patients with, or at risk of, atherosclerotic disease who were undergoing non-cardiac surgery to receive extended-release metoprolol succinate (n=4174) or placebo (n=4177), by a computerised randomisation phone service. Study treatment was started 2–4 h before surgery and continued for 30 days. Patients, health-care providers, data collectors, and outcome adjudicators were masked to treatment allocation. The primary endpoint was a composite of cardiovascular death, non-fatal myocardial infarction, and non-fatal cardiac arrest. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00182039.FindingsAll 8351 patients were included in analyses; 8331 (99·8%) patients completed the 30-day follow-up. Fewer patients in the metoprolol group than in the placebo group reached the primary endpoint (244 [5·8%] patients in the metoprolol group vs 290 [6·9%] in the placebo group; hazard ratio 0·84, 95% CI 0·70–0·99; p=0·0399). Fewer patients in the metoprolol group than in the placebo group had a myocardial infarction (176 [4·2%] vs 239 [5·7%] patients; 0·73, 0·60–0·89; p=0·0017). However, there were more deaths in the metoprolol group than in the placebo group (129 [3·1%] vs 97 [2·3%] patients; 1·33, 1·03–1·74; p=0·0317). More patients in the metoprolol group than in the placebo group had a stroke (41 [1·0%] vs 19 [0·5%] patients; 2·17, 1·26–3·74; p=0·0053).InterpretationOur results highlight the risk in assuming a perioperative β-blocker regimen has benefit without substantial harm, and the importance and need for large randomised trials in the perioperative setting. Patients are unlikely to accept the risks associated with perioperative extended-release metoprolol.FundingCanadian Institutes of Health Research; Commonwealth Government of Australia's National Health and Medical Research Council; Instituto de Salud Carlos III (Ministerio de Sanidad y Consumo), Spain; British Heart Foundation; AstraZeneca.

AIM: To investigate the effect of in vivo environment on gene expression in Helicobacter pylori (H. pylori) as it relates to its survival in the host. METHODS: In vivo expression technology (IVET) systems are used to identify microbial virulence genes. We modified the IVET-transcriptional fusion vector, pIVET8, which uses antibiotic resistance as the basis for selection of candidate genes in host tissues to develop two unique IVET-promoter-screening vectors, pIVET11 and pIVET12. Our novel IVET systems were developed by the fusion of random Sau3A DNA fragments of H. pylori and a tandem-reporter system of chloramphenicol acetyltransferase and beta-galactosidase. Additionally, each vector contains a kanamycin resistance gene. We used a mouse macrophage cell line, RAW 264.7 and mice, as selective media to identify specific genes that H. pylori expresses in vivo. Gene expression studies were conducted by infecting RAW 264.7 cells with H. pylori. This was followed by real time polymerase chain reaction (PCR) analysis to determine the relative expression levels of in vivo induced genes. RESULTS: In this study, we have identified 31 in vivo induced (ivi) genes in the initial screens. These 31 genes belong to several functional gene families, including several well-known virulence factors that are expressed by the bacterium in infected mouse stomachs. Virulence factors, vacA and cagA, were found in this screen and are known to play important roles in H. pylori infection, colonization and pathogenesis. Their detection validates the efficacy of these screening systems. Some of the identified ivi genes have already been implicated to play an important role in the pathogenesis of H. pylori and other bacterial pathogens such as Escherichia coli and Vibrio cholerae. Transcription profiles of all ivi genes were confirmed by real time PCR analysis of H. pylori RNA isolated from H. pylori infected RAW 264.7 macrophages. We compared the expression profile of H. pylori and RAW 264.7 coculture with that of H. pylori only. Some genes such as cagA, vacA, lpxC, murI, tlpC, trxB, sodB, tnpB, pgi, rbfA and infB showed a 2-20 fold upregulation. Statistically significant upregulation was obtained for all the above mentioned genes (P < 0.05). tlpC, cagA, vacA, sodB, rbfA, infB, tnpB, lpxC and murI were also significantly upregulated (P < 0.01). These data suggest a strong correlation between results obtained in vitro in the macrophage cell line and in the intact animal. CONCLUSION: The positive identification of these genes demonstrates that our IVET systems are powerful tools for studying H. pylori gene expression in the host environment.

Histiocytic diseases encompass a spectrum of proliferative diseases in humans and dogs. While these orphan malignancies are rare in the human, histiocytic diseases are relatively frequent in certain breeds of dog. In the dog, these diseases range from benign histiocytoma to malignant histiocytic sarcoma (HS). Disseminated HS has a poor prognosis and lacks effective treatment options in both humans and dogs. The overall goal of this study is to unravel the mechanisms of tumorigenesis in histiocytic diseases and identify better treatments. Our studies have focused on microRNAs (miRNAs), which are master regulators of gene expression and may have a significant role in tumorigenesis in histiocytic diseases. MiRNA profiling of canine histiocytic diseases was conducted on cases of reactive histiocytosis, HS, and hemophagocytic HS. These samples were compared to normal canine histiocytes derived from peripheral blood or peritoneal fluid. Several miRNAs were identified to be upregulated in the disease samples and were selected for validation by qRT-PCR. From these results, two miRNA targets were selected for further evaluation. We are probing the significance of the upregulation of these miRNAs by inhibiting their function in canine HS cell lines using chemical miRNA inhibitors and sponge constructs designed to competitively bind the upregulated miRNAs, thus preventing them from acting on their targets. Our results to date indicate that inhibiting these miRNAs in the canine HS cell line, DH82, decreases growth rate by as much as 39%. Studies into other aspects of tumorigenicity potentially affected by the inhibition of these miRNAs are underway. Our preliminary data suggests these miRNAs themselves may be effective therapeutic targets for histiocytic diseases. Additionally, further analysis of the pathways regulated by these miRNAs may identify critical gene targets in HS tumorigenesis and thus increase our understanding of these malignancies and discover novel and effective therapies. Comparative studies have the potential to provide opportunities for advancement in these orphan malignancies, and in this case, improve clinical outcome in dogs and humans. Citation Format: Emmalena J. Gregory-Bryson, Maciej Parys, Matti Kiupel, Vilma Yuzbasiyan-Gurkan. Effects of inhibition of upregulated microRNAs in canine histiocytic sarcoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4383. doi:10.1158/1538-7445.AM2014-4383

Mice which coexpress human papillomavirus type 16 E7 and HLA A2.1 in peripheral squamous epithelium and thymic cortical epithelium are tolerant at the cytotoxic T-lymphocyte (CTL) level to E7 epitopes restricted through HLA A*0201 and H-2 b (T. Doan, M. Chambers, M. Street, G. J. Fernando, K. Herd, P. Lambert, and R. Tindle, Virology 244:352–364, 1998). Here we used bone marrow-reconstituted radiation chimeras to distinguish whether E7-directed CTL tolerance was mediated peripherally by E7 expression in skin or centrally by E7 expression in thymus. In chimeric mice expressing E7 in skin and reconstituted with E7-naı̈ve bone marrow and E7-naı̈ve thymus, CTL responses to vaccine-administered E7 epitopes were not restored, i.e., the mice remained tolerant. In contrast, chimeric mice not expressing E7 in skin and reconstituted with E7-naı̈ve bone marrow and E7-expressing thymus had full E7-directed CTL responses. These results demonstrate that E7 protein expression in peripheral squamous epithelium is sufficient to tolerize the E7-directed CTL precursor repertoire. The data have implications for E7-mediated tumorigenesis and for the development of E7-based immunotherapeutic strategies, since peripheral immunological tolerance of tumor-associated antigens may create a barrier to effective immunotherapy.

Histiocytic diseases encompass a spectrum of proliferative diseases in humans and dogs. While relatively rare in the human, histiocytic diseases are quite prevalent in certain breeds of dog. In the dog, these diseases range from benign histiocytoma to the malignancy, histiocytic sarcoma (HS). Disseminated HS has a poor prognosis and lacks effective treatment options. The goal of this study is to unravel the mechanisms of tumorigenesis in histiocytic diseases by analyzing the differential expression of microRNAs (miRNAs) along the spectrum of canine histiocytic diseases. As regulators of gene expression, miRNAs will provide insight into the pathways for tumorigenesis in histiocytic malignancies as compared to benign histiocytic diseases. MiRNA profiling of canine histiocytic diseases was conducted on cases of reactive histiocytosis, histiocytic sarcoma, and hemophagocytic histiocytic sarcoma. These samples were compared to normal canine histiocytes derived from peripheral blood. Based upon analysis of the profiling data, several miRNAs were selected for verification and quantification by quantitative reverse transcription PCR. The expression of the known canine miRNAs was evaluated by miRNA array. Data analysis with unsupervised clustering resulted in miRNA expression pattern clusters that were similar to the disease groups. The miRNA profiling data revealed three miRNA targets that were significantly upregulated in all cases as compared to normal canine histiocytes. Functional studies of these miRNAs are underway. These findings support the hypothesis that each histiocytic disease entity has a unique miRNA profile. These miRNAs and/or genes in the pathways they regulate may be targeted for novel and effective therapies. Comparative studies have the potential to elucidate HS tumorigenesis, and improve clinical outcome in dogs and humans. Citation Format: Emmalena Gregory-Bryson, Maciej Parys, Matti Kiupel, Vilma Yuzbasiyan-Gurkan. Identification of critical microRNA regulated pathways in histiocytic diseases. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5288. doi:10.1158/1538-7445.AM2013-5288

Canine histiocytic sarcoma is an aggressive and uniformly-fatal round-cell neoplasm. The localized, peri-articular form of the disease (PAHS) appears to have statistically significant prolonged survival, when compared to the non - peri-articular form of the disease (non-PAHS). Knowledge of the molecular basis for the aggressiveness of the canine histiocytic sarcoma is foundational for developing effective treatments. The aim of this study was to characterize the molecular expression profiles of the different sub-types of the disease. Canine patients, with spontaneously-arising histiocytic sarcoma, were recruited for the study. Tumor tissue samples and peripheral blood were obtained and used for primary cell line development and gene expression analysis. Eight PAHS and 8 non-PAHS tumor samples were selected. RNA extraction, amplification and labeling were performed using standard techniques. Raw gene expression values were obtained using the Affymetrix GeneChip Canine Genome 2.0 Array. Background correction, normalization, PM correction, summarization, and expression analysis were performed using R/affy/limma. Gene set analysis was performed using BRB-ArrayTools, and the Molecular Signatures Database (MSigDB), to investigate gene ontology groups of genes whose expression was differentially regulated. Primary cell lines from tumor biopsies and peripheral blood samples were developed and characterized based on cellular morphology, growth characteristics, and immunophenotyping. In our gene expression array experiments, we identified specific gene transcripts that are more likely to represent true and biologically meaningful differences in expression levels between PAHS and non-PAHS. More specifically, metallopeptidase genes, and homeobox domain gene expression levels were enriched in the PAHS group, while ATP-binding cassette genes, and interleukin 1 receptor signaling gene expression levels were enriched in the non-PAHS group. Our results suggest presence of gene expression signatures that can provide insight in the diverse biologic behavior of the disease and highlight canine spontaneous tumors in understanding tumor biology. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5092. doi:1538-7445.AM2012-5092

Background: The objectives of the present study were: to determine the sensitivity and specificity of oral fluid testing compared with the performance of standard blood-based HIV enzyme immunoassay; to assess the feasibility of oral fluid specimen collection from clients for the purposes of HIV testing within a clinical setting; and to assess the clinical and laboratory impact regarding staffing, material resources, expertise and funding of oral fluid testing. Methods: A parallel comparative trial of oral fluid and blood testing was conducted among a group of HIV positive clients and a group of unknown HIV serostatus clients where each client was offered both tests. An ambulatory HIV clinic recruited 175 known HIV positive clients and 179 persons were recruited through an inner city sexual health clinic while attending for routine sexual health checks. Client responses to oral fluid collection were assessed. The sensitivity and specificity of oral fluid testing were calculated. Results: Of the 176 confirmed HIV reactive blood test results, the OraSure (OraSure Technologies, Beaverton, OR, USA) assay failed to detect only one of these, demonstrating a sensitivity of 99.4%. Of the 178 blood specimens that were tested as non-reactive by the AxSYM (Abbott Laboratories, Abbott Park, IL, USA) Combo system, OraSure recorded four of the corresponding oral fluid specimens as reactive (assumed to be false-positive), giving a specificity of 97.6%. Although evaluation of patients undergoing the test showed a large proportion (88.6%) preferred the OraSure test to conventional blood testing, a large minority of these (22.6%) made such a preference conditional on the OraSure test being as reliable as current blood testing. Conclusions: This limited clinic based trial of oral fluid testing for HIV antibodies among an outpatient population has demonstrated the potential of oral fluid as a specimen for HIV testing. However, the lower performance of the test compared with current serum-based tests may limit the usefulness of OraSure to epidemiological studies or as an alternative screening tool in outreach settings among higher risk populations.

BACKGROUND: Preoperative autologous blood donation is commonly used to reduce exposure to allogeneic transfusions among patients undergoing elective cardiac surgery. However, this technique is associated with an overall increase in transfusions (allogeneic or autologous). The authors assessed the impact of transfusion decision-making on the effectiveness of preoperative autologous donation in reducing the frequency of allogeneic transfusions, and its impact on the increased transfusion rate associated with preoperative autologous donation in cardiac surgery. METHODS: This retrospective analysis compared transfusion practices among 176 patients who predonated autologous blood before elective cardiac surgery and 176 matched cardiac surgery patients who did not predonate blood. The impact of decision-making on transfusion exposure was determined using multivariate analyses to account for major perioperative interventions and complications. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for exposure to allogeneic blood transfusion or any transfusion, before and after exclusion of transfusions not conforming with selected transfusion criteria. RESULTS: Exposure to allogeneic transfusion was more likely among patients who did not predonate blood than among those who did predonate blood (OR 14.0, 95% CI 5.8-33.8). This finding was still true after exclusion of transfusions not meeting the transfusion criteria (OR 19.3, 95% CI 6.7-55.7). The autologous blood donors were more likely than the nondonors to receive any transfusion (OR 10.8, 95% CI 5.7-20.3). However, this association was substantially attenuated after exclusion of transfusions not meeting the transfusion criteria (OR 1.9, 95% CI 1.1-3.2). INTERPRETATION: Patients who predonated blood before elective cardiac surgery were at lower risk of receiving allogeneic transfusions than the nondonors. This was not because of a deliberate withholding of allogeneic transfusions from autologous donors. However, more liberal transfusion criteria for autologous blood were largely responsible for the increased transfusion rate among the autologous donors.