Outcomes following perioperative red blood cell transfusion in patients undergoing elective major abdominal surgery: a systematic review and meta-analysis.

BACKGROUND: Perioperative red blood cell transfusion is a double-edged sword for surgical patients. While transfusion of red cells can increase oxygen delivery by increasing haemoglobin levels, its impact on short- and long-term postoperative outcomes, particularly in patients undergoing elective major abdominal surgery, is unclear. METHODS: We conducted a systematic review and meta-analysis on the effect of perioperative blood transfusions on postoperative outcomes in elective major abdominal surgery. PubMed, Cochrane, and Scopus databases were searched for studies with data collected between January 1, 2000 and June 6, 2020. The primary outcome was short-term mortality, including all-cause 30-day or in-hospital mortality. Secondary outcomes included long-term all-cause mortality, any morbidity, infectious complications, overall survival, and recurrence-free survival. No randomised controlled trials were found. Thirty-nine observational studies were identified, of which 37 were included in the meta-analysis. RESULTS: Perioperative blood transfusion was associated with short-term all-cause mortality (odds ratio [OR] 2.72, 95% confidence interval [CI] 1.89-3.91, P<0.001), long-term all-cause mortality (hazard ratio 1.35, 95% CI 1.09-1.67, P=0.007), any morbidity (OR 2.18, 95% CI 1.81-2.64, P<0.001), and infectious complications (OR 1.90, 95% CI 1.60-2.26, P<0.001). Perioperative blood transfusion remained associated with short-term mortality in the sensitivity analysis after excluding studies that did not control for preoperative anaemia (OR 2.27, 95% CI 1.59-3.24, P<0.001). CONCLUSIONS: Perioperative blood transfusion in patients undergoing elective major abdominal surgery is associated with poorer short- and long-term postoperative outcomes. This highlights the need to implement patient blood management strategies to manage and preserve the patient's own blood and reduce the need for red blood cell transfusion. TRIAL REGISTRATION: PROSPERO (CRD42021254360).

Clinical and molecular epidemiology of community-onset invasive Staphylococcus aureus infection in New Zealand children.

Our aim was to describe the epidemiology and incidence of community-onset invasive S. aureus disease in children presenting to our hospital, and to compare the clonal complexes and virulence genes of S. aureus strains causing invasive and non-invasive disease. The virulence gene repertoire of invasive disease isolates was characterized using DNA microarray and compared with the virulence gene repertoire of non-invasive S. aureus isolates. Over the study period, 163 children had an invasive S. aureus infection. There was no difference in the distribution of clonal complexes or in the prevalence of genes encoding virulence factors between invasive and non-invasive isolates. Future research should include a strong focus on identifying the host and environmental factors that, along with organism virulence factors, are contributing to the patterns of invasive S. aureus disease observed in New Zealand.

Mesenteric blood flow, glucose absorption and blood pressure responses to small intestinal glucose in critically ill patients older than 65 years.

PURPOSE: To compare nutrient-stimulated changes in superior mesenteric artery (SMA) blood flow, glucose absorption and glycaemia in individuals older than 65 years with, and without, critical illness. METHODS: Following a 1-h 'observation' period (t (0)-t (60)), 0.9 % saline and glucose (1 kcal/ml) were infused directly into the small intestine at 2 ml/min between t (60)-t (120), and t (120)-t (180), respectively. SMA blood flow was measured using Doppler ultrasonography at t (60) (fasting), t (90) and t (150) and is presented as raw values and nutrient-stimulated increment from baseline (Δ). Glucose absorption was evaluated using serum 3-O-methylglucose (3-OMG) concentrations during, and for 1 h after, the glucose infusion (i.e. t (120)-t (180) and t (120)-t (240)). Mean arterial pressure was recorded between t (60)-t (240). Data are presented as median (25th, 75th percentile). RESULTS: Eleven mechanically ventilated critically ill patients [age 75 (69, 79) years] and nine healthy volunteers [70 (68, 77) years] were studied. The magnitude of the nutrient-stimulated increase in SMA flow was markedly less in the critically ill when compared with healthy subjects [Δt (150): patients 115 (-138, 367) versus health 836 (618, 1,054) ml/min; P = 0.001]. In patients, glucose absorption was reduced during, and for 1 h after, the glucose infusion when compared with health [AUC(120-180): 4.571 (2.591, 6.551) versus 11.307 (8.447, 14.167) mmol/l min; P < 0.001 and AUC(120-240): 26.5 (17.7, 35.3) versus 40.6 (31.7, 49.4) mmol/l min; P = 0.031]. A close relationship between the nutrient-stimulated increment in SMA flow and glucose absorption was evident (3-OMG AUC(120-180) and ∆SMA flow at t (150): r (2) = 0.29; P < 0.05). CONCLUSIONS: In critically ill patients aged >65 years, stimulation of SMA flow by small intestinal glucose infusion may be attenuated, which could account for the reduction in glucose absorption.

Incidence, diagnosis, and outcomes of vocal fold immobility after esophageal atresia (EA) and/or tracheoesophageal fistula (TEF) repair.

BACKGROUND: The diagnosis of vocal fold paralysis in an infant is a devastating finding that may require a permanent tracheotomy. The incidence of congenital vocal fold paralysis is unknown, but it is thought to be more common in infants with anatomic anomalies in the aero-digestive system. Vocal fold paralysis after surgical repair of esophageal atresia and tracheoesophageal fistula is a rare finding often diagnosed after multiple failed extubations. Currently infants do not routinely undergo documentation of vocal fold motion prior to esophageal atresia repair. We report here on our experience with this rare complication. METHOD: A retrospective review was done of patients with esophageal atresia and/or tracheoesophageal fistula from 1985 to 2009. Patient demographics, operative techniques, and outcomes were collected. RESULTS: 150 patients were identified. Mean age at surgical intervention was 12 ± 33 days. Otolaryngology service was consulted for 13% of patients with postoperative failure. Awake fiberoptic laryngoscopy identified 3% of patients with vocal fold paralysis. Bilateral vocal fold paralysis was found in 3 patients, and 2 patients had unilateral vocal fold paralysis. Patients with bilateral paralysis were treated with tracheotomy; unilateral paralysis was treated expectantly. CONCLUSION: In this study, 3% of patients were diagnosed with vocal fold paralysis after esophageal atresia repair. The etiology of vocal fold paralysis in this study is difficult to assess. Pre-operative fiberoptic laryngoscopy is recommended to identify children with congenital vocal fold paralysis prior to surgical intervention, especially in those requiring revision surgery.

Bowel obstruction after treatment of intra-abdominal tumors.

BACKGROUND: Tumors of the solid viscera are one of the most common types of pediatric malignancies. Due to the intra-abdominal location of many of these neoplasms, laparotomy and/or bowel resection are often necessary, predisposing patients to postoperative intestinal obstruction. Additionally, chemotherapy and radiation therapy may lead to acute and chronic bowel injury, also potentially predisposing these patients to postoperative bowel obstruction. We reviewed our data over an eleven-year period to identify the incidence of obstruction as well as factors associated with its development. METHODS: A retrospective data analysis of all patients diagnosed with intra-abdominal Wilms' tumor, rhabdomyosarcoma, neuroblastoma, and Hodgkin's and non-Hodgkin's lymphoma in a single institution from 1997 to 2007 was conducted. Data collected included demographic factors, operations, incidence of small bowel obstruction (SBO) and the use of adjuvant or neoadjuvant chemoradiation therapy. Patients who developed SBO were compared to those who did not develop obstruction. Data comparisons were analyzed statistically using Fisher's exact test, 2-tailed Student's t-Test, or chi-square proportional analysis with significance reported for p<0.05. RESULTS: A total of 291 patients were identified during the study period. Mean age at diagnosis was 8.1+/-5.8 years. Males accounted for 57% of all patients. Tumor distribution was as follows: Wilms' tumor: 56 (19%); non-Hodgkin's lymphoma: 71 (24%); Hodgkin's lymphoma: 64 (22%); rhabdomyosarcoma: 32 (11%); and neuroblastoma: 68 (24%). There were a total of 12 bowel obstructions in 11 patients (3.7%). Mean follow-up for all patients was 3.6+/-2.7 years. Children with bowel obstruction were more likely to be male (4.5:1, p=0.061) and younger (4.2 years versus 8.1 years; p=0.087). Wilms' tumor accounted for 45% of patients with bowel obstruction, but made up only 19% of the study population. The incidence of bowel obstruction in patients with Wilms' tumor was 8.9% compared to an overall incidence of 3.8% (p=0.043). CONCLUSION: Bowel obstruction is relatively uncommon after intra-abdominal malignancies in children. Wilms' tumor, rhabdomyosarcoma and Burkitt's lymphoma appear to be associated with the highest risk of bowel obstruction.

Effects of glucokinase activators GKA50 and LY2121260 on proliferation and apoptosis in pancreatic INS-1 beta cells.

AIMS/HYPOTHESIS: Glucokinase (GK), an enzyme that phosphorylates glucose to form glucose 6-phosphate, serves as the glucose sensor that regulates insulin secretion in beta cells. GK activators (GKAs) activate GK via binding to an allosteric site of the enzyme. GKAs increase glucose-stimulated insulin secretion and decrease blood glucose levels. Using the differentiated beta cell line INS-1, we investigated the role of GKAs in promoting beta cell growth and survival and preventing beta cell apoptosis induced by chronic exposure to high levels of glucose. METHODS: Proliferation was assessed using BrdU incorporation. Apoptosis was measured using caspase-3 activity. Immunoblot analysis was used to detect protein levels and the degree of phosphorylation. RESULTS: The GK agonists GKA50 and LY2121260 increased both cell replication and cell numbers when tested at basal levels of glucose (3 mmol/l) in INS-1 cells. GKAs promoted INS-1 cell proliferation via upregulation of insulin receptor substrate-2 and subsequent activation of protein kinase B phosphorylation. GKA50 also prevented the INS-1 cell apoptosis that was induced by chronic high glucose conditions, probably via an increase in GK protein levels and normalisation of the apoptotic protein BCL2-associated agonist of cell death (BAD) and its phosphorylation. As a result of the reduction in cell apoptosis, GKA50 prevented cell loss and maintained glucose-stimulated insulin secretion. In addition, the anti-apoptotic activity of GKA50 was significantly abrogated by other GKAs that do not inhibit apoptosis, suggesting that direct binding of GKA50 to GK is essential for its anti-apoptotic effect. CONCLUSION/INTERPRETATION: Our results suggest novel roles of GKAs in promoting beta cell growth and preventing chronic-hyperglycaemia-induced beta cell apoptosis. Thus, GKAs may provide novel therapeutics that increase beta cell mass to maintain euglycaemia in diabetes.

Education, training and support needs of Australian trained doctors and international medical graduates in rural Australia: a case of special needs?

INTRODUCTION: Little attention has been paid to issues relating to the education, training and support needs of Australian medical graduates and international medical graduates (IMGs) in rural practices. The focus continues to be on recruiting to rural areas. The aim of this article was to document the education, training and support needs of rural GPs. METHODS: Cross-sectional surveys were made of rural GPs working in rural north-west New South Wales, Australia. The main outcome measures were the key factors influencing rural GPs to stay in rural practice. RESULTS: Australian medical graduates and IMGs largely agree on key education, training and professional support needs. Continuing professional development, training opportunities, professional support and networking, as well as financial support are the doctors' shared top priority issues. Rural GPs satisfied with their current medical practice, intend to remain in rural practice for 40% longer than those who are not satisfied (11.5 years compared with 8.2 years). Rural GPs contented with their life as a rural doctor intend to remain in rural practice for 51% longer than those who are discontented (11.8 years compared with 7.8 years). CONCLUSION: While there is merit in delivering specially designed initiatives to target groups, such as male or female GPs, registrars or GPs, our results support the notion that IMGs should not so much be considered to have special needs, but rather an integral part of the region's medical workforce.

Estradiol prevents amyloid-beta peptide-induced cell death in a cholinergic cell line via modulation of a classical estrogen receptor.

The pathology of Alzheimer's disease includes amyloid-beta peptide aggregation that contributes to degeneration of cholinergic neurons. Even though the underlying molecular mechanisms remain unclear, recent in vitro evidence supports a protective role for estrogens against several neurotoxic agents. Here we report that, in a murine cholinergic cell line (SN56), the massive cell death induced by 1-40 fragment of amyloid-beta peptide was prevented by 17beta-estradiol through a mechanism that may involve estrogen receptor activation. The protective effect of estradiol was observed in a dose-dependent manner, and was completely blocked by the pure antiestrogen ICI 182,780. In contrast, the inactive isomer 17alpha-estradiol consistently showed weaker neuroprotection than the native hormone that was unaffected by ICI 182,780 treatment. In addition, equivalent concentrations of 17beta-estradiol enhanced luciferase activity in cells transfected with a luciferase reporter gene driven by tandem estrogen response elements. Estrogen-induced luciferase activity was blocked by ICI 182,780, indicating estrogen receptor-dependent transcriptional activity. We also observed by reverse transcription-polymerase chain reaction, Western blot and immunocytochemistry that increasing concentrations of 17beta-estradiol enhanced the expression of estrogen receptor alpha mRNA and protein during amyloid-beta-induced toxicity. Under these conditions, it was found by confocal microscopy that the localization of estrogen receptor alpha in the absence of hormone was mainly extranuclear. However, the receptor was consistently observed also at the nuclear region after estrogen exposure. Overall, these data suggest that estrogen may exert neuroprotective effects against amyloid-beta-induced toxicity by activation of estrogen receptor-mediated pathways. In addition, intracellular estrogen receptors are up-regulated by their cognate hormone even during exposure to neurotoxic agents.

Immunological and biochemical characterization of streptococcal pyrogenic exotoxins I and J (SPE-I and SPE-J) from Streptococcus pyogenes.

Recently, we described the identification of novel streptococcal superantigens (SAgs) by mining the Streptococcus pyogenes M1 genome database at Oklahoma University. Here, we report the cloning, expression, and functional analysis of streptococcal pyrogenic exotoxin (SPE)-J and another novel SAg (SPE-I). SPE-I is most closely related to SPE-H and staphylococcal enterotoxin I, whereas SPE-J is most closely related to SPE-C. Recombinant forms of SPE-I and SPE-J were mitogenic for PBL, both reaching half maximum responses at 0.1 pg/ml. Evidence from binding studies and cell aggregation assays using a human B-lymphoblastoid cell line (LG-2) suggests that both toxins exclusively bind to the polymorphic MHC class II beta-chain in a zinc-dependent mode but not to the generic MHC class II alpha-chain. The results from analysis by light scattering indicate that SPE-J exists as a dimer in solution above concentrations of 4.0 mg/ml. Moreover, SPE-J induced a rapid homotypic aggregation of LG-2 cells, suggesting that this toxin might cross-link MHC class II molecules on the cell surface by building tetramers of the type HLA-DRbeta-SPE-J-SPE-J-HLA-DRbeta. SPE-I preferably stimulates T cells bearing the Vbeta18.1 TCR, which is not targeted by any other known SAG: SPE-J almost exclusively stimulates Vbeta2.1 T cells, a Vbeta that is targeted by several other streptococcal SAgs, suggesting a specific role for this T cell subpopulation in immune defense. Despite a primary sequence diversity of 51%, SPE-J is functionally indistinguishable from SPE-C and might play a role in streptococcal disease, which has previously been addressed to SPE-C.

Superantigen recognition by gammadelta T cells: SEA recognition site for human Vgamma2 T cell receptors.

Human gammadelta T cells expressing the Vgamma2Vdelta2 antigen receptors recognize nonpeptide prenyl pyrophosphate and alkylamine antigens. We find that they also recognize staphylococcal enterotoxin A superantigens in a manner distinct from the recognition of nonpeptide antigens. Using chimeric and mutant toxins, SEA amino acid residues 20-27 were shown to be required for gammadelta TCR recognition of SEA. Residues at 200-207 that are critical for specific alphabeta TCR recognition of SEA do not affect gammadelta TCR recognition. SEA residues 20-27 are located in an area contiguous with the binding site of V beta chains. This study defines a superantigen recognition site for a gammadelta T cell receptor and demonstrates the differences between Vgamma2Vdelta2+ T cell recognition of superantigens and nonpeptide antigens.

Conservation and variation in superantigen structure and activity highlighted by the three-dimensional structures of two new superantigens from Streptococcus pyogenes.

Bacterial superantigens (SAgs) are a structurally related group of protein toxins secreted by Staphylococcus aureus and Streptococcus pyogenes. They are implicated in a range of human pathologies associated with bacterial infection whose symptoms result from SAg-mediated stimulation of a large number (2-20%) of T-cells. At the molecular level, bacterial SAgs bind to major histocompatability class II (MHC-II) molecules and disrupt the normal interaction between MHC-II and T-cell receptors (TCRs). We have determined high-resolution crystal structures of two newly identified streptococcal superantigens, SPE-H and SMEZ-2. Both structures conform to the generic bacterial superantigen folding pattern, comprising an OB-fold N-terminal domain and a beta-grasp C-terminal domain. SPE-H and SMEZ-2 also display very similar zinc-binding sites on the outer concave surfaces of their C-terminal domains. Structural comparisons with other SAgs identify two structural sub-families. Sub-families are related by conserved core residues and demarcated by variable binding surfaces for MHC-II and TCR. SMEZ-2 is most closely related to the streptococcal SAg SPE-C, and together they constitute one structural sub-family. In contrast, SPE-H appears to be a hybrid whose N-terminal domain is most closely related to the SEB sub-family and whose C-terminal domain is most closely related to the SPE-C/SMEZ-2 sub-family. MHC-II binding for both SPE-H and SMEZ-2 is mediated by the zinc ion at their C-terminal face, whereas the generic N-terminal domain MHC-II binding site found on many SAgs appears not to be present. Structural comparisons provide evidence for variations in TCR binding between SPE-H, SMEZ-2 and other members of the SAg family; the extreme potency of SMEZ-2 (active at 10(-15) g ml-1 levels) is likely to be related to its TCR binding properties. The smez gene shows allelic variation that maps onto a considerable proportion of the protein surface. This allelic variation, coupled with the varied binding modes of SAgs to MHC-II and TCR, highlights the pressure on SAgs to avoid host immune defences.

The streptococcal superantigen SMEZ exhibits wide allelic variation, mosaic structure, and significant antigenic variation.

The frequencies of the newly identified streptococcal superantigen genes smez, spe-g, and spe-h were determined in a panel of 103 clinical isolates collected between 1976 and 1998 at various locations throughout New Zealand. smez and spe-g were found in every group A Streptococcus (GAS) isolate, suggesting a chromosomal location. The spe-h gene was found in only 24% of the GAS isolates and is probably located on a mobile DNA element. The smez gene displays extensive allelic variation and appears to be in linkage equilibrium with the M/emm type. 22 novel smez alleles were identified from 21 different M/emm types in addition to the already reported alleles smez and smez-2 with sequence identities between 94. 5 and 99.9%. Three alleles are nonfunctional due to a single base pair deletion. The remaining 21 alleles encode distinct SMEZ variants. The mosaic structure of the smez gene suggests that this polymorphism has arisen from homologous recombination events rather than random point mutation. The recently resolved SMEZ-2 crystal structure shows that the polymorphic residues are mainly surface exposed and scattered over the entire protein. The allelic variation did not affect either Vbeta specificity or potency, but did result in significant antigenic differences. Neutralizing antibody responses of individual human sera against different SMEZ variants varied significantly. 98% of sera completely neutralized SMEZ-1, but only 85% neutralized SMEZ-2, a very potent variant that has not yet been found in any New Zealand isolate. SMEZ-specific Vbeta8 activity was found in culture supernatants of 66% of the GAS isolates, indicating a potential base for the development of a SMEZ targeting vaccine.

Guidelines for pacemaker follow-up in Canada: a consensus statement of the Canadian Working Group on Cardiac Pacing.

A survey on Canadian pacing practices conducted in 1997 revealed a widespread desire for national guidelines on pacemaker follow-up. The present guidelines for pacemaker follow-up are a consensus statement of the Canadian Working Group on Cardiac Pacing. Direct patient follow-up rather than transtelephonic monitoring is desirable. Patients should be assessed at a minimum of within 72 h of implantation, at two to 12 weeks and at six months following implantation, and annually thereafter. More frequent assessments may be required for some patients. This depends on associated cardiovascular problems and specific devices. A typical follow-up visit should include a targeted cardiovascular assessment, interrogation of the pacing system, review of telemetered data, assessment of the underlying rhythm, assessment of pacing and sensing thresholds, and appropriate reprogramming of pacing parameters to optimize device function and longevity.

Superantigens in human disease.

Superantigens have been implicated in a wide variety of human diseases. Yet, solid evidence for their role in pathogenesis is available only for Toxic Shock Syndrome and a few other conditions. This evidence is critically reviewed herein.

Deep venous thrombosis: recent advances and optimal investigation with US.

Compression US is the imaging procedure of choice for patients with clinically suspected DVT of the lower and upper extremities. Clinical trials have validated the safety of the approach of relying on two negative US studies obtained 1 week apart to safely exclude the diagnosis of DVT. In selected low-risk patients, the diagnosis of DVT may be excluded by a single negative US study. US has a role to play in the management of patients with suspected pulmonary embolism who have nondiagnostic pulmonary imaging studies.

Identification and characterization of novel superantigens from Streptococcus pyogenes.

Three novel streptococcal superantigen genes (spe-g, spe-h, and spe-j) were identified from the Streptococcus pyogenes M1 genomic database at the University of Oklahoma. A fourth novel gene (smez-2) was isolated from the S. pyogenes strain 2035, based on sequence homology to the streptococcal mitogenic exotoxin z (smez) gene. SMEZ-2, SPE-G, and SPE-J are most closely related to SMEZ and streptococcal pyrogenic exotoxin (SPE)-C, whereas SPE-H is most similar to the staphylococcal toxins than to any other streptococcal toxin. Recombinant (r)SMEZ, rSMEZ-2, rSPE-G, and rSPE-H were mitogenic for human peripheral blood lymphocytes with half-maximal responses between 0.02 and 50 pg/ml (rSMEZ-2 and rSPE-H, respectively). SMEZ-2 is the most potent superantigen (SAg) discovered thus far. All toxins, except rSPE-G, were active on murine T cells, but with reduced potency. Binding to a human B-lymphoblastoid line was shown to be zinc dependent with high binding affinity of 15-65 nM. Evidence from modeled protein structures and competitive binding experiments suggest that high affinity binding of each toxin is to the major histocompatibility complex class II beta chain. Competition for binding between toxins was varied and revealed overlapping but discrete binding to subsets of class II molecules in the hierarchical order (SMEZ, SPE-C) > SMEZ-2 > SPE-H > SPE-G. The most common targets for the novel SAgs were human Vbeta2.1- and Vbeta4-expressing T cells. This might reflect a specific role for this subset of Vbetas in the immune defense of gram-positive bacteria.

Substituted tetrahydropyrrolo[2,1-b]oxazol-5(6H)-ones and tetrahydropyrrolo[2,1-b]thiazol-5(6H)-ones as hypoglycemic agents.

A series of substituted tetrahydropyrrolo[2,1-b]oxazol-5(6H)-ones and tetrahydropyrrolo[2,1-b]thiazol-5(6H)-ones was synthesized from amino alcohols or amino thiols and keto acids. A pharmacological model based on the results obtained with these compounds led to the synthesis and evaluation of a series of isoxazoles and other monocyclic compounds. These were evaluated for their ability to enhance glucose utilization in cultured L6 myocytes. The in vivo hypoglycemic efficacy and potency of these compounds were evaluated in a model of type 2 diabetes mellitus (non-insulin-dependent diabetes mellitus), the ob/ob mouse. 25a(2S) (SDZ PGU 693) was selected for further pharmacological studies.

Cardiac pacing in Canada in 1998: working towards optimal pacing therapy. Canadian Working Group on Cardiac Pacing.

The Canadian Working Group on Cardiac Pacing (CWGCP) was formed in 1996 with the primary goal of promoting optimal pacing therapy in Canada. In 1997, the CWGCP conducted a survey of pacing practices across Canada. Ninety-two of 125 implanting programs (74%) responded. Implant rates vary by province--from 39 per 100,00 population in Ontario to 63 per 100,000 population in Nova Scotia and Prince Edward Island. Variations in regional implant rates persist even after correcting for the age of the population. Physiological pacing was used for 35% of all implants in Canada in 1996/97. There were marked differences across Canada in the mode of pacing selected. In western Canada, 39.5% of pacing systems implanted were physiological compared with 18.2% in Atlantic Canada and 29% in Quebec. There were also differences in follow-up practices. Approximately 40% of centres follow patients with single chamber pacemakers annually, whereas most other centres still follow these patients every six months. Economic constraints, the size of pacing programs and the involvement of committed pacing physicians are factors that may influence the regional differences in cardiac pacing across Canada.