Search

Alterations to the gut microbiome have been linked to multiple chronic diseases. However, the drivers of such changes remain largely unknown. The oral cavity acts as a major route of exposure to exogenous factors including pathogens, and processes therein may affect the communities in the subsequent compartments of the gastrointestinal tract. Here, we perform strain-resolved, integrated meta-genomic, transcriptomic, and proteomic analyses of paired saliva and stool samples collected from 35 individuals from eight families with multiple cases of type 1 diabetes mellitus (T1DM).We identified distinct oral microbiota mostly reflecting competition between streptococcal species. More specifically, we found a decreased abundance of the commensal Streptococcus salivarius in the oral cavity of T1DM individuals, which is linked to its apparent competition with the pathobiont Streptococcus mutans. The decrease in S. salivarius in the oral cavity was also associated with its decrease in the gut as well as higher abundances in facultative anaerobes including Enterobacteria. In addition, we found evidence of gut inflammation in T1DM as reflected in the expression profiles of the Enterobacteria as well as in the human gut proteome. Finally, we were able to follow transmitted strain-variants from the oral cavity to the gut at the individual omic levels, highlighting not only the transfer, but also the activity of the transmitted taxa along the gastrointestinal tract.Alterations of the oral microbiome in the context of T1DM impact the microbial communities in the lower gut, in particular through the reduction of "mouth-to-gut" transfer of Streptococcus salivarius. Our results indicate that the observed oral-cavity-driven gut microbiome changes may contribute towards the inflammatory processes involved in T1DM. Through the integration of multi-omic analyses, we resolve strain-variant "mouth-to-gut" transfer in a disease context. Video Abstract.

Vaginal microbiota composition affects many facets of reproductive health. Lactobacillus iners-dominated microbial communities are associated with poorer outcomes, including higher risk of bacterial vaginosis (BV), compared with vaginal microbiota rich in L. crispatus. Unfortunately, standard-of-care metronidazole therapy for BV typically results in dominance of L. iners, probably contributing to post-treatment relapse. Here we generate an L. iners isolate collection comprising 34 previously unreported isolates from 14 South African women with and without BV and 4 previously unreported isolates from 3 US women. We also report an associated genome catalogue comprising 1,218 vaginal Lactobacillus isolate genomes and metagenome-assembled genomes from300 women across 4 continents. We show that, unlike L. crispatus, L. iners growth is dependent on L-cysteine in vitro and we trace this phenotype to the absence of canonical cysteine biosynthesis pathways and a restricted repertoire of cysteine-related transport mechanisms. We further show that cysteine concentrations in cervicovaginal lavage samples correlate with Lactobacillus abundance in vivo and that cystine uptake inhibitors selectively inhibit L. iners growth in vitro. Combining an inhibitor with metronidazole promotes L. crispatus dominance of defined BV-like communities in vitro by suppressing L. iners growth. Our findings enable a better understanding of L. iners biology and suggest candidate treatments to modulate the vaginal microbiota to improve reproductive health for women globally.

As the primary genetic determinant of immune recognition of self and non-self, the hyperpolymorphic HLA genes play key roles in disease association and transplantation. The large, variably sized HLA class II genes have historically been less well characterized than the shorter HLA class I genes. Here, we have used Pacific Biosciences Single Molecule Real-Time (SMRT®) DNA sequencing to perform four-field resolution HLA typing of HLA-DRB1/3/4/5, -DQA1, -DQB1, -DPA1 and -DPB1 from a panel of 181 B-lymphoblastoid cell lines from the International HLA and Immunogenetics Workshops. By interrogating all exons, introns, and the untranslated regions of these important reference cells, we have improved their HLA typing resolution on the IPD-IMGT/HLA database. We observed widespread non-coding polymorphism, with over twice as many unique genomic sequences identified compared with coding sequences (CDS). We submitted 263 unique sequences to the IPD-IMGT/HLA Database, often from multiple cell lines, including 114 confirmations of existing alleles, of which 30 were also extensions to full-length genomic sequences where only CDS was available previously. A total of 149 novel alleles were identified, largely differing from their closest reference allele sequences by a single nucleotide polymorphism (SNP). However, some highly divergent alleles were deemed to be recombinants, only detectable by full-length sequencing with long, phased reads. The fourth-field variation we observed allowed fine mapping of linkage disequilibrium patterns and haplotypes to particular ancestries. This study has highlighted the under-appreciated non-coding diversity in HLA class II genes, with potential implications for population genetic and clinical studies.

Cervicovaginal bacterial communities composed of diverse anaerobes with low Lactobacillus abundance are associated with poor reproductive outcomes such as preterm birth, infertility, cervicitis, and risk of sexually transmitted infections (STIs), including human immunodeficiency virus (HIV). Women in sub-Saharan Africa have a higher prevalence of these high-risk bacterial communities when compared to Western populations. However, the transition of cervicovaginal communities between high- and low-risk community states over time is not well described in African populations.We profiled the bacterial composition of 316 cervicovaginal swabs collected at 3-month intervals from 88 healthy young Black South African women with a median follow-up of 9 months per participant and developed a Markov-based model of transition dynamics that accurately predicted bacterial composition within a broader cross-sectional cohort. We found that Lactobacillus iners-dominant, but not Lactobacillus crispatus-dominant, communities have a high probability of transitioning to high-risk states. Simulating clinical interventions by manipulating the underlying transition probabilities, our model predicts that the population prevalence of low-risk microbial communities could most effectively be increased by manipulating the movement between L. iners- and L. crispatus-dominant communities.The Markov model we present here indicates that L. iners-dominant communities have a high probability of transitioning to higher-risk states. We additionally identify transitions to target to increase the prevalence of L. crispatus-dominant communities. These findings may help guide future intervention strategies targeted at reducing bacteria-associated adverse reproductive outcomes among women living in sub-Saharan Africa. Video Abstract.

The microbiome of the female genital tract (FGT) is closely linked to reproductive health outcomes. Diverse, anaerobe-dominated communities with low Lactobacillus abundance are associated with a number of adverse reproductive outcomes, such as preterm birth, cervical dysplasia, and sexually transmitted infections (STIs), including HIV. Vaginal dysbiosis is associated with local mucosal inflammation, which likely serves as a biological mediator of poor reproductive outcomes. Yet the precise mechanisms of this FGT inflammation remain unclear. Studies in humans have been complicated by confounding demographic, behavioral, and clinical variables. Specifically, hormonal contraception is associated both with changes in the vaginal microbiome and with mucosal inflammation. In this study, we examined the transcriptional landscape of cervical cell populations in a cohort of South African women with differing vaginal microbial community types. We also investigate effects of reproductive hormones on the transcriptional profiles of cervical cells, focusing on the contraceptive depot medroxyprogesterone acetate (DMPA), the most common form of contraception in sub-Saharan Africa. We found that antigen presenting cells (APCs) are key mediators of microbiome associated FGT inflammation. We also found that DMPA is associated with significant transcriptional changes across multiple cell lineages, with some shared and some distinct pathways compared to the inflammatory signature seen with dysbiosis. These results highlight the importance of an integrated, systems-level approach to understanding host-microbe interactions, with an appreciation for important variables, such as reproductive hormones, in the complex system of the FGT mucosa.

In evaluation research, "programs" are often conceptualized as clearly bounded, narrow in scope, focused on specific outcomes, using a well-defined linear causal model, and hence, suitable for standard evaluation methods. The evaluation work reported here was carried out in a more challenging context, where large, complex, interwoven systems were targets for change as a means to influence a diffuse array of outcomes. Our evaluation of an NIH-funded program to improve statewide infrastructure for clinical and translational health research ("Advance-CTR") used qualitative data provided by investigators who used the program's services, were funded awardees, or were members of an internal advisory committee (leadership representatives from partnering institutions). We examined perceived barriers to systemic changes to enhance research, as well as how systems have changed due to the Rhode Island Advance-CTR program's efforts, to what degree, and with what effects. Using the causal logic of our program to connect these more distal systemic outcomes to the services and components of Advance-CTR, we discuss the effects this program has had on researchers and their environments, contributing to the development of sustainable programs of research that ultimately improve the health and well-being of our state's residents.

Background We compared vaginal microbial communities in postmenopausal black and white women. Methods Shotgun sequencing of vaginal swabs from postmenopausal women self-identified as black or white was compared using MiRKAT. Results Vaginal community dominance by Lactobacillus crispatus or Lactobacillusgasseri was more common in 44 postmenopausal black women (n = 12, 27%) than among 44 matched white women (n = 2, 5%; P = .01). No individual taxa were significantly more abundant in either group. Conclusions We identified small overall differences in vaginal microbial communities of black and white postmenopausal women. L. crispatus dominance was more common in black women. Clinical Trials Registration NCT02516202 (MsFLASH05) and NCT01418209 (MsFLASH03).

Importance. Observational studies have suggested that the use of radial artery grafts for coronary artery bypass grafting may improve clinical outcomes compared with the use of saphenous vein grafts, but this has not been confirmed in randomized trials.Objective. To compare clinical outcomes between patients receiving radial artery or saphenous vein grafts for coronary artery bypass grafting at long-term follow-up.Design, Setting, and Participants. Patient-level pooled analysis comparing radial artery and saphenous vein grafts in adult patients undergoing isolated coronary artery bypass grafting from five countries (Australia, Italy, Serbia, South Korea, and United Kingdom; enrollment years: 1997 to 2009, follow-up completed in 2019).Intervention. Patients were randomized to receive either radial artery or saphenous vein grafts for coronary artery bypass grafting.Main outcomes and measures. The primary outcome was a composite of death, myocardial infarction or repeat revascularization, and the secondary outcome was a composite of death or myocardial infarction.Results. 1036 patients (534 radial artery group) were randomized (mean age 66.6 vs 67.1 years, males 70.4% vs 69.9% in the radial artery and the saphenous vein groups, respectively); 942 (90.9%) of the originally randomized patients completed 10 years of follow-up (510 radial artery group). At a median follow-up of 10 years (interquartile range 10-11), the use of the radial artery was associated with a statistically significant reduction in the incidence of the composite outcome of death, myocardial infarction or repeat revascularization (220 vs 237 events; 41 vs 47 events per 1000 patient-years; hazard ratio[HR] 0.73, 95%confidence interval[CI] 0.61-0.88, pConclusions and relevance. In this individual participant data meta-analysis with a median follow up of 10 years, among patients undergoing coronary artery bypass grafting, the use of the radial artery compared with saphenous vein grafts was associated with a lower risk of a composite of cardiovascular outcomes.

A change in cardiac surgery practice over the past decade has seen an increase in urgent or inpatient referrals for surgery, with antiplatelet therapy often continued up until surgery. This study aims to identify the optimal timing for administration of aspirin to minimise risk of perioperative morbidity and mortality.From a prospectively compiled database collected by the Australian and New Zealand Society of Cardiac and Thoracic Surgeons, we identified 8294 patients undertaking combined CABG and valve or isolated valve procedures while discontinuing aspirin. Time points for cessation of antiplatelet therapy were categorised as follows:2 days, 3-7 days or7 days preoperatively. We evaluated the association of adverse in-hospital events and intermediate term survival in each time category.Discontinuing aspirin 3 to 7 days from surgery decreased rates of perioperative MI (HR=0.300, p=0.027), return to theatre (HR=0.560, p=0.002) reduced drain output (HR=0.757, p=0.000) and red blood cell and platelet transfusions (HR=0.719, p=0.000 and HR=0.604, p=0.000 respectively) compared to patients continuing aspirin until2 days from the procedure. Stopping aspirin2 days from the date of surgery increased risk of perioperative MI (HR=5.919, p=0.000), reoperation for bleeding (HR=2.076, p=0.001), returning to theatre (HR=1.781, p=0.000), ICC drain losses (HR=1.337, p=0.000) and transfusion demands for red blood cells (HR=1.381, p=0.000) and platelets (HR=1.450, p=0.000) when compared to those discontinuing aspirin7 days from surgery.Late discontinuation of aspirin before combined coronary artery bypass graft and valve procedures results in greater rates of bleeding and transfusion requirements. Earlier discontinuation of aspirin results in no benefit in intermediate term survival.

The hyperpolymorphic HLA genes play important roles in disease and transplantation and act as genetic markers of migration and evolution. A panel of 107 B-lymphoblastoid cell lines (B-LCLs) was established in 1987 at the 10th International Histocompatibility Workshop as a resource for the immunogenetics community. These B-LCLs are well characterised and represent diverse ethnicities and HLA haplotypes. Here we have applied Pacific Biosciences' Single Molecule Real-Time (SMRT) DNA sequencing to HLA type 126 B-LCL, including the 107 International HLA and Immunogenetics Workshop (IHIW) cells, to ultra-high resolution. Amplicon sequencing of full-length HLA class I genes (HLA-A, -B and -C) and partial length HLA class II genes (HLA-DRB1, -DQB1 and -DPB1) was performed. We typed a total of 931 HLA alleles, 895 (96%) of which were consistent with the typing in the IPD-IMGT/HLA Database (Release 3.27.0, January 20, 2017), with 595 (64%) typed at a higher resolution. Discrepant types, including novel alleles (n = 10) and changes in zygosity (n = 13), as well as previously unreported types (n = 34) were observed. In addition, patterns of linkage disequilibrium were distinguished by four-field resolution typing of HLA-B and HLA-C. By improving and standardising the HLA typing of these B-LCLs, we have ensured their continued usefulness as a resource for the immunogenetics community in the age of next generation DNA sequencing.

Objectives To compare the physiology of apneic oxygenation with low-tidal-volume (VT) ventilation during harvesting of the left internal mammary artery. Design Prospective, single-center, randomized trial. Setting Single-center teaching hospital. Participants The study comprised 24 patients who underwent elective coronary artery bypass grafting surgery. Interventions Apneic oxygenation (apneic group: 12 participants) and low-VT ventilation (low-VT group: 12 participants) (2.5 mL/kg ideal body weight) for 15 minutes during harvesting of the left internal mammary artery. Measurement and Main Results The primary endpoint was an absolute change in partial pressure of arterial carbon dioxide (PaCO2). Secondary endpoints were changes in arterial pH, pulmonary artery pressures (PAP), cardiac index, and pulmonary artery acceleration time and ease of surgical access. The mean (standard deviation) absolute increase in PaCO2 was 31.8 mmHg (7.6) in the apneic group and 17.6 mmHg (8.2) in the low-VT group (baseline-adjusted difference 14.2 mmHg [95% confidence interval 21.0-7.3], p

International audience; Technical variation in metagenomic analysis must be minimized to confidently assess the contributions of microbiota to human health. Here we tested 21 representative DNA extraction protocols on the same fecal samples and quantified differences in observed microbial community composition. We compared them with differences due to library preparation and sample storage, which we contrasted with observed biological variation within the same specimen or within an individual over time. We found that DNA extraction had the largest effect on the outcome of metagenomic analysis. To rank DNA extraction protocols, we considered resulting DNA quantity and quality, and we ascertained biases in estimates of community diversity and the ratio between Gram-positive and Gram-negative bacteria. We recommend a standardized DNA extraction method for human fecal samples, for which transferability across labs was established and which was further benchmarked using a mock community of known composition. Its adoption will improve comparability of human gut microbiome studies and facilitate meta-analyses.

It is generally accepted that radial artery (RA) grafts have better mid-term patency rate compared to saphenous vein grafts. However, the clinical correlates of the improved patency rate are still debated. Observational studies have suggested increased survival and event-free survival for patients who receive an RA rather than a saphenous vein, but they are open to bias and confounders. The only evidence based on randomized data is a pooled meta-analysis of 6 randomized controlled trial comparing the RA and the saphenous vein published by the RADial artery International Alliance (RADIAL). In the RADIAL database, improved freedom from follow-up cardiac events (death, myocardial infarction and repeat revascularization) was found at 5-year follow-up in the RA arm. The most important limitation of the RADIAL analysis is that most of the included trials had an angiographic follow-up in the first 5 years and it is unclear whether the rate of repeat revascularization (the main driver of the composite outcome) was clinically indicated due to per-protocol angiographies. Here, we present the protocol for the long-term analysis of the RADIAL database. By extending the follow-up beyond the 5th postoperative year (all trials except 1 did not have angiographic follow-up beyond 5 years), we aim to provide data on the role of RA in coronary artery bypass surgery with respect to long-term outcomes.

Background We used a large patient-level data set including 6 angiographic randomized controlled trials (RCTs) on coronary artery bypass conduits to explore incidence and determinants of coronary graft failure. Methods Patient-level angiographic data of 6 RCTs comparing long-term outcomes of the radial artery and other conduits were joined. Primary outcome was graft occlusion at maximum follow-up. The analysis was divided as (1) left anterior descending coronary (LAD) distribution and (2) non-LAD distribution (circumflex and right coronary artery). Mixed-model multivariable Cox regression including all baseline characteristics with stratification by individual trials was used to identify predictors of graft occlusion. Results Included were 1091 patients and 2281 grafts, consisting of 921 left internal mammary arteries, 74 right internal mammary arteries, 710 radial arteries, and 576 saphenous veins. All left internal mammary arteries were used on the LAD, the other conduits were used on the non-LAD distribution. Mean angiographic follow up was 65 ± 29 months. Occlusion rates were 2.3% for the left internal mammary arteries, 13.5% for the left internal mammary arteries, 9.4% for the right internal mammary arteries, and 17.5% for the saphenous veins. At multivariable analysis, type of conduit used, age, female sex, left ventricular ejection fraction of less than 0.50, and use of the Y graft were significantly associated with graft occlusion in the non-LAD distribution. Conclusions Our analyses showed that failure of the left internal mammary arteries-to-LAD bypass is a very uncommon event. For the non-LAD distribution, the nonuse of radial artery, age, female sex, left ventricular ejection fraction of less than 0.50, and use of the Y graft configuration were significantly associated with midterm graft failure.

Phosphoinositide 3-kinase (PI3K) plays an integral role in lymphocyte function. Mutations in PIK3CD and PIK3R1, encoding the PI3K p110δ and p85α subunits, respectively, cause increased PI3K activity and result in immunodeficiency with immune dysregulation. We describe here the first cases of disseminated and congenital toxoplasmosis in a mother and child who share a pathogenic mutation in PIK3R1 and review the mechanisms underlying susceptibility to severe Toxoplasma gondii infection in activated PI3Kδ syndrome (APDS) and in other forms of primary immunodeficiency.

B cell receptors (BCRs) display a combination of variable (V)-gene-encoded complementarity determining regions (CDRs) and adaptive/hypervariable CDR3 loops to engage antigens. It has long been proposed that the former tune for recognition of pathogens or groups of pathogens. To experimentally evaluate this within the human antibody repertoire, we perform immune challenges in transgenic mice that bear diverse human CDR3 and light chains but are constrained to different human VH-genes. We find that, of six commonly deployed VH sequences, only those CDRs encoded by IGHV1-2∗02 enable polyclonal antibody responses against bacterial lipopolysaccharide (LPS) when introduced to the bloodstream. The LPS is from diverse strains of gram-negative bacteria, and the VH-gene-dependent responses are directed against the non-variable and universal saccrolipid substructure of this antigen. This reveals a broad-spectrum anti-LPS response in which germline-encoded CDRs naturally hardwire the human antibody repertoire for recognition of a conserved microbial target., Graphical Abstract, Highlights • Transgenic mice alter VH-gene contribution to human-like BCR repertoires • Specific human VH-genes are needed to engage bloodborne bacterial LPS in vivo • Germline-endowed antigen recognition targets a universally conserved LPS moiety, The ligand binding surface of antibodies is generated by diverse gene-encoded and hypervariable loops. Sangesland et al. demonstrate that certain gene-encoded loops are needed for human antibodies to accommodate the shapes of some bacterial antigens and naturally tune for recognition of conserved microbial features therein.

FOXN1 is the master regulatory gene of thymic epithelium development. FOXN1 deficiency leads to thymic aplasia, alopecia, and nail dystrophy, accounting for the nude/severe combined immunodeficiency (nu/SCID) phenotype in humans and mice. We identified several newborns with low levels of Tcell receptor excision circles (TRECs) and Tcell lymphopenia at birth, who carried heterozygous loss-of-function FOXN1 variants. Longitudinal analysis showed persistent Tcell lymphopenia during infancy, often associated with nail dystrophy. Adult individuals with heterozygous FOXN1 variants had in most cases normal CD4+ but lower than normal CD8+ cellcounts. We hypothesized a FOXN1 gene dosage effect on the function of thymic epithelial cells (TECs) and thymopoiesis and postulated that these effects would be more prominent early in life. To test this hypothesis, we analyzed TEC subset frequency and phenotype, early thymic progenitor (ETP) cell count, and expression of FOXN1 target genes (Ccl25, Cxcl12, Dll4, Scf, Psmb11, Prss16, and Cd83) in Foxn1nu/+ (nu/+) mice and age-matched wild-type (+/+) littermate controls. Both the frequency and the absolute count of ETP were significantly reduced in nu/+ mice up to 3weeks of age. Analysis of the TEC compartment showed reduced expression of FOXN1 target genes and delayed maturation of the medullary TEC compartment in nu/+ mice. These observations establish a FOXN1 gene dosage effect on thymic function and identify FOXN1 haploinsufficiency as an important genetic determinant of Tcell lymphopenia at birth.

Background Gut microbes influence their hosts in many ways, in particular by modulating the impact of diet. These effects have been studied most extensively in humans and mice. In this work, we used whole genome metagenomics to investigate the relationship between the gut metagenomes of dogs, humans, mice, and pigs. Results We present a dog gut microbiome gene catalog containing 1,247,405 genes (based on 129 metagenomes and a total of 1.9 terabasepairs of sequencing data). Based on this catalog and taxonomic abundance profiling, we show that the dog microbiome is closer to the human microbiome than the microbiome of either pigs or mice. To investigate this similarity in terms of response to dietary changes, we report on a randomized intervention with two diets (high-protein/low-carbohydrate vs. lower protein/higher carbohydrate). We show that diet has a large and reproducible effect on the dog microbiome, independent of breed or sex. Moreover, the responses were in agreement with those observed in previous human studies. Conclusions We conclude that findings in dogs may be predictive of human microbiome results. In particular, a novel finding is that overweight or obese dogs experience larger compositional shifts than lean dogs in response to a high-protein diet. Electronic supplementary material The online version of this article (10.1186/s40168-018-0450-3) contains supplementary material, which is available to authorized users.

ObjectivesCoronary artery disease has been viewed as a relentless, progressive disease. We sought to describe the prevalence and distribution of regression of native vessel disease in coronary artery bypass patients and characterize its relationship with bypass grafting.MethodsAmong 619 patients who underwent bypass surgery in a radial artery trial, 405 had follow-up angiography available a mean of 6.2 ± 3.1 years (range, 0-14) after surgery. The percentage of diameter stenosis of each major native coronary vessel was reported by 3 cardiac specialists and classified into grades of nonflow limiting (0%-39%), moderate (40%-69%), flow limiting (70%-80%), severely stenosed (81%-99%), and occluded (100%). Native vessel disease regression was defined as decrease in 1 or more grades of stenosis between the pre- and postoperative angiograms.ResultsA total of 1742 native coronary arteries had preoperative stenosis of at least 40% and were included in the present analysis, receiving 753 arterial grafts and 391 saphenous vein grafts. Overall, the prevalence of disease regression was 19.7%, and 45% of patients demonstrated regression in 1 or more vessels. The presence of an arterial graft increased the likelihood of disease regression (21.3% compared with 16% for venous bypassed vessels, P = .012) as did the location in the left circulation (22.6% compared with 13.9% for the right circulation, P

Hypereosinophilic syndrome (HES) is a rare systemic condition, defined as a persistently elevated eosinophil count associated with end organ damage and the absence of a primary cause. Cardiac involvement occurs in about 50% of patients with HES. Myocardial infiltration results in endomyocardial fibrosis, valve dysfunction and mural thrombus. The atrioventricular valves are almost always involved, resulting in regurgitation due to leaflet restriction, most commonly affecting the posterior mitral valve leaflet. Surgical management remains challenging in patients with HES with limited data on the choice of valve surgery. We describe the case of a 17-year-old woman with HES complicated by congestive cardiac failure secondary to severe mitral and tricuspid regurgitation. Because of refractory heart failure despite medical therapy, surgical mitral and tricuspid valve repair was performed, and an excellent 24-month outcome was achieved. We believe this is the first report of double valve repair in this rare condition.

Australian and New Zealand Society of Cardiac and Thoracic Surgeons, Sydney, Australia Cardiothoracic Surgical Unit, Royal Prince Alfred Hospital; The Baird Institute; University of Sydney, Sydney, Australia Department of Cardiothoracic Surgery, Royal Melbourne Hospital; Department of Surgery, University of Melbourne Victorian Heart Centre, Epworth Hospital; Department of Cardiac Surgery, Austin Hospital; University of Melbourne, Melbourne, Australia Department of Cardiothoracic Surgery, Monash Health and Department of Surgery (Monash Medical Centre), Monash University, Clayton, Victoria, Australia Department of Cardiothoracic Surgery, Westmead Hospital, Sydney, Australia

Context: Cardiac surgery.Objective: To compare plasma and urinary neutrophil gelatinase-associated lipocalin (P-/U-NGAL) in on-pump (n = 43) versus off-pump (n = 40) surgery.Materials and methods: We obtained perioperative P-/U-NGAL and outcome data.Results: P-/U-NGAL increased after surgery. P-NGAL was higher post-surgery in on pump patients (139 versus 67 µg L−1; p

OBJECTIVES: We evaluated the influence of lipid exposure upon conduit patency in long-term follow-up after primary CABG. METHODS: From a prospectively compiled database, we identified 1207 grafts (436 SV and 771 mixed arterial grafts) among 413 CABG patients with 9.4 ± 2.4 years of follow-up (range 3–13). Surveillance angiography was performed as part of a randomized trial. All available lipid assays were collected from pathology laboratories, and from these, mean annualized lipid exposure was calculated for total cholesterol, HDL, LDL and triglycerides. Angiographical and clinical data were analysed against lipid exposure. Graft failure was defined as occlusion, string sign or >80% stenosis. RESULTS: Six thousand and seventy-seven lipid measurements were obtained, and there were 154 failed grafts. Three hundred and eleven patients received at least one vein graft, and all 413 patients received at least one arterial graft. Overall, only HDL levels were inversely correlated with graft failure, with total cholesterol and LDL showing no associations in a mixed pool of arterial and venous grafts. To assess whether total/LDL cholesterol had no effect or were exerting competing effects in arteries and veins, separate multivariate analyses were performed. Venous graft failure was associated with increased total cholesterol/HDL (P= 0.006) and LDL/HDL (P= 0.032). By contrast, elevated total cholesterol was correlated with a reduced risk of arterial graft failure (OR for graft failure 0.705, P= 0.023) with increasing LDL cholesterol following a similar trend (OR for graft failure 0.729, P= 0.051). CONCLUSION: Sub-fractions of dyslipidaemia known to be risk factors for native vessel disease appear to similarly influence vein grafts. Arterial conduits are at least more resistant to the effects of high lipid exposure, and appear to be protective. These results favour the use of arterial grafts in patients with poorly controlled dyslipidaemia.

ObjectiveThe radial artery (RA) has gained popularity as a conduit for coronary artery bypass surgery despite a paucity of patient-centered analysis of long-term quality of life after its removal. We sought to characterize forearm function and symptoms after RA harvest and compare these with those associated with saphenous vein (SV) removal.MethodsA total of 408 patients from an RA trial completed a questionnaire up to 14 years after primary coronary artery bypass surgery. The survey included 7 statements concerning hand and forearm symptoms or limitations in daily life and 4 questions on concerns associated with arm or leg scars. A total of 230 patients had received an RA graft (RA group). Responses were graded in order of severity from 0 to 7, with greater than 3 (mild concern) being regarded as a significant symptom. Mean response to each question and total scores were compared with the non-RA harvest group. Comparisons were also made with responses to the same questionnaire completed preoperatively and 3 months postoperatively. In patients who had both RA and SV removal, we compared the impact of a forearm scar on quality of life with that of a leg scar.ResultsThe mean duration of follow-up was 9.3 years (range, 4–14 years), and the response rate was 83%. In the RA group, 92% to 99% reported no significant symptoms, with the most frequent concerns relating to pain and numbness (8% each), but this was not significantly higher than in those who had not had an RA harvested. In the RA group, the mean scores for scar appearance and discomfort were 0.95 and 0.93, respectively (where 1 = no concern), suggesting satisfactory cosmesis and no impact on function. Symptom severity was significantly worse in 6 of 7 questions when compared with preoperative responses and in 4 of 7 items compared with 3-month follow-up, indicating a general deterioration in function over long-term follow-up. In those who had both the RA and SV harvested, patients reported more scar discomfort associated with SV harvest at 3 months (1.69 vs 1.34, P

Objective Whether to graft a moderately stenosed coronary vessel remains debatable. We investigated whether grafting such vessels is warranted based on angiographic evidence of disease progression. Methods Of 619 patients who underwent on-pump coronary artery bypass grafting in an ongoing, randomized radial artery trial, 405 have at least 1 follow-up angiogram at a mean of 6.2 ± 3.1 years (range, 0-14 years) after surgery. Percent diameter stenosis in each major native vessel was reported by 3 cardiac specialists and classified as either moderate (40%-69%) or severe (≥70%) stenosis. Progression of native vessel disease and graft patency were determined by comparison of pre- and postoperative angiography. Results A total of 3816 native vessels and 1242 bypass grafts were analyzed, of which 386 moderate preoperative lesions were identified, 323 of which were grafted. In all territories, grafted vessels had greater risk of disease progression than ungrafted equivalents (43.4% vs 10.5%, P 001). Moderate lesions were more likely than severe lesions to remain unchanged on follow-up angiography (52.6% vs 31.1%, P 001). Only 1 in 7 moderate lesions in the right coronary artery exhibited significant progression during follow-up if left ungrafted, whereas the likelihood of progression in left-sided counterparts approached 50%. Arterial and vein grafts to left-sided moderately stenosed vessels had excellent patency (83% and 77% at 8 years, respectively), which was not matched by right-sided grafts ( P = .051). Placement of a graft for a moderate lesion was associated with significantly greater incidence of disease progression, most marked in the right coronary territory. Conclusions The greater risk of progression of left-sided moderate lesions, and high graft patency rates when bypassed, suggests that the balance of clinical judgment lies in favor of grafting moderate left-sided lesions. In the right coronary system, however, a lesion is likely to remain moderate if left ungrafted and, with a low risk of progression, it may be reasonable to leave these vessels undisturbed.

Short-term mortality prediction models have an important role in current cardiac surgical practice. There has been much less attention paid to prediction of long-term outcomes which are probably an equal marker both of surgeon performance and appropriateness of surgical treatment. The aim of this study was to assess the performance of the New York State Cardiac Surgery Reporting System (NYSCSRS) risk model and the Northern New England Cardiovascular Disease Study Group (NNECDSG) risk model on the Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) patient database.The NYSCSRS and the NNECDSG risk models were applied to all patients undergoing isolated coronary artery bypass graft (CABG) surgery that had complete data, were over the age of 18 and had a body mass index between 12 and 78 kg/m2. Predicted mortality was calculated using the published risk model formulae and compared with observed mortality, obtained via linkage with the National Death Index, at four time-points (one, three, five and seven years following surgery). Model discrimination and model calibration were tested at all four time points by determining the C-statistics for receiver operator characteristic (ROC) curves, and studying the Hosmer-Lemeshow chi-square tests, respectively.The NYSCSRS and NNECDSG risk models were applied to 34,961 and 34,998 patients, respectively. The NYSCSRS risk model over-predicted mortality by between 130% and 216% at all four time-points while the NNECDSG risk model under-predicted mortality at one year by 4.3% but over-predicted mortality at three, five and seven years by between 42.5% and 145.7%. The C-statistics obtained fell between 0.779 and 0.741 for the NYSCSRS risk model and between 0.785 and 0.752 for the NNECDSG risk model at all four time-points. Hosmer-Lemeshow chi-square tests returned p-values0.001 at all four time-points for both risk models.The NYSCSRS and NNECDSG risk models do not accurately predict long-term mortality following isolated CABG surgery in the ANZSCTS patient population. The use of either of these risk models is not appropriate in Australia.

Background The Salmonella enterica serovar Derby is frequently isolated from pigs and turkeys whereas serovar Mbandaka is frequently isolated from cattle, chickens and animal feed in the UK. Through comparative genomics, phenomics and mutant construction we previously suggested possible mechanistic reasons why these serovars demonstrate apparently distinct host ranges. Here, we investigate the genetic and phenotypic diversity of these two serovars in the UK. We produce a phylogenetic reconstruction and perform several biochemical assays on isolates of S. Derby and S. Mbandaka acquired from sites across the UK between the years 2000 and 2010. Results We show that UK isolates of S. Mbandaka comprise of one clonal lineage which is adapted to proficient utilisation of metabolites found in soya beans under ambient conditions. We also show that this clonal lineage forms a biofilm at 25 °C, suggesting that this serovar maybe well adapted to survival ex vivo, growing in animal feed. Conversely, we show that S. Derby is made of two distinct lineages, L1 and L2. These lineages differ genotypically and phenotypically, being divided by the presence and absence of SPI-23 and the ability to more proficiently invade porcine jejunum derived cell line IPEC-J2. Conclusion The results of this study lend support to the hypothesis that the differences in host ranges of S. Derby and S. Mbandaka are adaptations to pathogenesis, environmental persistence, as well as utilisation of metabolites abundant in their respective host environments. Electronic supplementary material The online version of this article (doi:10.1186/s12866-016-0628-4) contains supplementary material, which is available to authorized users.

Prosthesis-patient mismatch (PPM) is characterised by the effects of inadequate prosthesis size relative to body surface area (BSA). It is uncertain whether PPM after mitral valve replacement impacts upon clinical outcome. This was examined in an Australian population.From 2001 to 2009, 1006 mechanical and bioprosthetic mitral valves were implanted across 10 institutions. Effective orifice areas (EOA) were obtained from a literature review of in vivo echocardiographic data. Absent, moderate and severe PPM was defined as an indexed EOA (EOA/BSA) of1.20 cm(2)/m(2),0.90 to ≤1.20 cm(2)/m(2) and ≤0.9 cm(2)/m(2), respectively. Early outcomes and 7-year survival were compared between these three groups.PPM was absent in 34%, moderate in 53% and severe in 13% of patients. Patients with PPM were more likely to be male (42% vs 52% vs 62%, p0.0001) and obese (14% vs 20% vs 56%, p0.0001). Postoperatively there was similar 30-day mortality (5% vs 5% vs 6%, p=0.83) and early any mortality/morbidity (24% vs 27% vs 29%, p=0.40). Seven-year survival was similar between groups (72±4.1% vs 76±3.2% vs 69±10.3%, p=0.76). PPM did not predict adverse events after logistic and Cox regressions with and without propensity score adjustment. Subgroup analyses of those with isolated mitral valve surgery, patients with preoperative congestive heart failure and non-obese patients failed to show an association between PPM and mid-term mortality.Overall, PPM was not associated with poorer early outcomes or mid-term survival. Oversizing valves may be technically hazardous and do not yield superior outcomes. Easier implantation by appropriate sizing appears justified.

Background Renal impairment is a major risk factor for cardiovascular disease. This study addressed clinical predictors of outcome following cardiac surgery, focusing on pre-operative renal dysfunction. Methods All patients undergoing cardiac surgery at Austin Health from June 1, 2001 to June 30, 2006, were included in the analysis. Logistic regression models were used to evaluate clinical factors predicting “operative mortality” and common post-operative complications. Results The operative mortality was 1.36% for coronary artery bypass grafting (CABG) alone (n = 1027), 5.07% for valve surgery alone (n = 217), 4.43% for combined CABG and valve surgery (n = 158) and 11.11% for other cardiac surgical procedures (n = 270). Amongst CABG alone patients, pre-operative renal impairment was a strong predictor of operative mortality, with a 35–43% increased risk of death (p = 0.005) for every 10 ml/min/1.73 m2 that the glomerular filtration rate was lower. Peripheral vascular disease, recent myocardial infarction and congestive cardiac failure also predicted operative mortality. Pre-operative renal impairment also increased the rate of various post-operative complications, as well as duration of admission. Conclusion Renal dysfunction is significantly associated with increased mortality and morbidity following cardiac surgery and necessitates careful consideration in risk benefit analysis when considering cardiac surgery.

Varicella-zoster virus (VZV)–specific cell-mediated immunity responses are essential for recovery from primary (varicella) or reactivation (herpes zoster) infection with VZV [1-4]. Patients who lack adequate VZV-specific cell-mediated immunity often have severe and prolonged infections with VZV, some of which are fatal [3-5]. Thus, VZV-specific cell-mediated immunity is a marker for protection against primary VZV infection, and the presence and magnitude of this response correlates with recovery from varicella and with the incidence and severity of reactivation as manifested by herpes zoster. VZV-specific cell-mediated immunity is also a component of primary responses to varicella vaccine administered to susceptible children and adults and has been used to evaluate candidate vaccines to prevent herpes zoster in immunocompromised and elderly individuals [6-9]. In this report, we present a regression model of VZV-specific memory CD4 responses as a function of age, from early childhood to advanced adulthood among healthy individuals with prior VZV wild-type infectionas a reference against which responses of other select groups of individuals are compared. Comparisons are made to elderly recipients of a zoster vaccine and to human immunodeficiency virus (HIV)–infected children and adults. We demonstrate that VZV-specific cell-mediated immunity is determined by the nature of primary immunization (natural infection vs VZV vaccination) and the age and immune status of the subject tested.

To evaluate the effectiveness of Opalescence PF 10% just after treatment, at 6-month follow-up and at a 14-month follow-up period.Opalescence PF 10% was applied nightly for 14 days. The color of teeth 11 and 21 of 17 subjects were measured with a spectrophotometer (L*; a*; b*) before treatment, just after treatment (14 days), after 6 months and after 14 months. Subjects were instructed to take note of any tooth sensitivity.For all three components (L*, a* and b*) statistical significant differences (p0.05) in the values between base-line, after treatment (14 days later), after 6 months and after 14 months were found (Wilcoxon Signed Rank Sum Test). The decrease in L* was about 20% after 6 months and about 50% after 14 months. The a* value decreased approximately 14% after 6 months but was worse after 14 months than at the beginning. The b* value decreased the least with about 9% after 6 months and about 8% after 14 months. The decrease in DeltaE(ab)(*) was approximately 20% after 14 months. Less than 20% of the subjects experienced mild tooth sensitivity just after treatment.Significantly whiter teeth were found after treatment as well as after a 6-month follow-up period. The whiteness/brightness (L*) decreased with approximately 50% after 14 months and the a* value with approximately 50% after 7 months, while the yellowness (b* value) remained even after 14 months.The product is an effective tooth whitener resulting in only low tooth sensitivity. Re-bleaching could be done at about 14 months.

Objective To investigate the optimum conduit for coronary targets other than the left anterior descending artery, we evaluated long-term patencies and clinical outcomes of the radial artery, right internal thoracic artery, and saphenous vein through the Radial Artery Patency and Clinical Outcomes trial. Methods As part of a 10-year prospective, randomized, single-center trial, patients undergoing primary coronary surgery were allocated to the radial artery (n = 198) or free right internal thoracic artery (n = 196) if aged less than 70 years (group 1), or radial artery (n = 113) or saphenous vein (n = 112) if aged at least 70 years (group 2). All patients received a left internal thoracic artery to the left anterior descending, and the randomized conduit was used to graft the second largest target. Protocol-directed angiography has been performed at randomly assigned intervals, weighted toward the end of the study period. Grafts are defined as failed if there was occlusion, string sign, or greater than 80% stenosis, independently reported by 3 assessors. Analysis is by intention to treat. Results At mean follow up of 5.5 years, protocol angiography has been performed in groups 1 and 2 in 237 and 113 patients, respectively. There are no significant differences within each group in preoperative comorbidity, age, or urgency. Patencies were similar for either of the 2 conduits in each group (log rank analysis, P = .06 and P = .54, respectively). The differences in estimated 5-year patencies were 6.6% (radial minus right internal thoracic artery) in group 1 and 2.9% (radial minus saphenous vein graft) in group 2. Conclusion At mean 5-year angiography in largely asymptomatic patients, the selection of arterial or venous conduit for the second graft has not significantly affected patency. This finding offers surgeons, for now, enhanced flexibility in planning revascularization.

Objectives: In order to determine the best conduit for coronary targets other than the left anterior descending (LAD) artery, long-term clinical outcomes following revascularisation with a radial artery or saphenous vein graft were evaluated as part of the radial artery patency and clinical outcomes (RAPCO) study. Methods: As part of the RAPCO protocol for this prospective, randomised, single-centre trial, patients aged over 70 years undergoing primary CABG were randomly assigned to use of a radial artery (n = 113) or saphenous vein (n = 112) to revascularise the best non-LAD coronary vessel. Follow-up was annual. Primary clinical end-points were death, myocardial infarction or need for revascularisation. Data were analysed by intention to treat. Results: The preoperative demographics (age, gender, presence of hypertension or diabetes mellitus) and urgency of surgery did not differ significantly between the two groups. The allocated arterial or venous conduit was utilised as intended in 104/ 113 and 110/112 patients, respectively. Mean number of grafts was 3.2 ±0.9 and 3.3 ± 0.7 in the two groups. During follow-up of mean duration 6.2 years (maximum 10.8 years) there were 16 deaths in each group and 9 vs 13 other events in the radial artery and saphenous vein groups, respectively. These clinical outcomes did not differ significantly (log rank p = 0.98 for survival and p = 0.52 for event-free survival). Conclusions: Use of a radial artery or saphenous vein for the second graft during primary CABG does not significantly influence clinical outcome at 6 years. Mean 5-year angiographic patency data are awaited, but from the patient's perspective the likelihood of a satisfactory long-term result is equivalent, whichever conduit is used.

Herpes zoster (HZ) is an often painful neurocutaneous syndrome resulting from reactivation of varicella-zoster virus (VZV) that has remained latent in sensory ganglia after primary VZV infection (varicella) [1–3]. The frequency and severity of HZ and its most common debilitating complication, postherpetic neuralgia (PHN), increase with age [4–9]. This age-related increase in disease correlates closely with the decline in VZV-specific T cell mediated immunity (VZV-CMI) that accompanies aging [10–14]. It is very unlikely that antibodies to VZV play a role in this relationship, because they do not decline with aging [13, 14]. Furthermore, HZ frequently occurs in circumstances when VZV-CMI is depressed while levels of VZV antibody are maintained by intravenous γ-globulin, such as those following hematopoietic stem cell transplantation [15–17] On the basis of these observations, it was hypothesized that HZ might be prevented or attenuated (i.e., less pain and PHN) in elderly individuals if their waning VZV-CMI could be boosted with a VZV vaccine [18–20]. Pilot studies indicated that VZV-CMI could be boosted in subjects ⩾60 years old with live attenuated Oka strain VZV vaccines [13, 14, 21, 22]. Subsequent trials demonstrated the safety and immunogenicity of a high-potency Oka/Merck VZV vaccine in elderly subjects, including persons with diabetes and chronic lung disease, and established the optimal vaccine formulation and potency (M.J. Levin et al., unpublished data) A double-blind, placebo-controlled trial (Veterans Affairs Cooperative Study 403: “The Shingles Prevention Study”) that involved 38,546 subjects ⩾60 years of age demonstrated that a high potency live attenuated Oka/Merck VZV vaccine (hereafter, “zoster vaccine”) significantly reduced the burden of illness due to HZ, understood in terms of a severity-by-duration measure of HZ pain and discomfort (i.e., the vaccine decreased the incidence of HZ and decreased the average severity of HZ in vaccinees who developed HZ), and substantially reduced the incidence of PHN in vaccine recipients [9]. The trial included an immunology substudy in which a subset of subjects had immunologic assessments performed before and after vaccination. We describe here the magnitude and kinetics of VZV-specific immune responses to zoster vaccine measured during the immunology substudy and their possible association with the occurrence of HZ

Background To investigate the optimum revascularization conduit for coronary territories other than that of the left anterior descending artery, long-term clinical outcomes after use of a radial artery or right internal thoracic artery were evaluated as part of the Radial Artery Patency and Clinical Outcomes (RAPCO) study. Methods As part of a 10-year prospective randomized single-center trial, patients aged less than 70 years undergoing primary coronary surgery were randomly allocated to the use of the radial artery (n = 198) or free right internal thoracic artery (n = 196) for grafting the largest target other than the left anterior descending artery. Annual follow-up documented death, myocardial infarction, or revascularization as primary endpoints. Analysis was on an intention-to-treat basis. Results There were no significant differences in the preoperative status of the two groups including age, sex, diabetes mellitus, hypertension, and urgency of surgery. One hundred eighty-six of 198 patients in the radial artery group and 179 of 196 patients in the right internal thoracic artery group received the intended conduit. Mean number of grafts was 3.1 ± 0.8 and 3.2 ± 0.9 in the radial artery and the right internal thoracic artery groups, respectively. During surveillance of as long as 10.4 years (mean, 6.0), absolute survival and event-free survival were equivalent between groups, with 13 versus 18 deaths and 24 versus 37 events (death, myocardial infarction, or revascularization) in the radial artery and the right internal thoracic artery groups, respectively (log rank: p = 0.36 for survival, p = 0.08 for event-free survival). Conclusions These two arterial conduits may yield equivalent clinical outcomes at 5 or more years. That finding will be compared with mean 5-year angiographic patency when available. For now, equivalent clinical results offer surgeons flexibility in planning revascularization.

The genomic sequence of the novel HLA-B*44:220 allele identified in a British Caucasoid male.

Total arterial revascularization (TAR) with internal thoracic arteries (ITAs) and radial arteries (RA) is associated with greater long-term survival compared with the use of a single internal thoracic artery supplemented by veins. The optimal conduit choice and configuration in achieving TAR remains controversial, with uncertainty regarding the individual prognostic impact of ITAs and RAs. As such, among patients solely undergoing TAR, we compared long-term survival between patients receiving single thoracic arteries and those receiving bilateral ITAs.From 1995 to 2010, 2821 patients with 3-vessel coronary artery disease at 8 centers underwent primary isolated coronary artery bypass with TAR using ITAs and RAs. Bilateral ITAs were used in 912 patients. In 380 cases, bilateral in situ ITAs were grafted to the left coronary system. RAs were used in 848 patients (93%) receiving bilateral ITAs and 1906 patients (99.8%) receiving single ITAs. Survival data were obtained using the National Death Index. Separate 1:1 propensity score-matched analyses were performed for (1) bilateral ITA versus single ITA and (2) bilateral ITA incorporating a free right ITA versus single ITA and RAs. Among the 912 patients with bilateral ITAs, those receiving an in situ right ITA to the left coronary system were compared with those receiving a free right ITA.In the propensity score-matched analysis comparing bilateral versus single ITAs (591 matched pairs), there were similar rates of 30-day mortality and deep sternal wound infection. Bilateral ITA use was associated with greater 15-year survival (79% ± 3.9% vs 67% ± 4.7%, P.001). In the analysis between bilateral ITA incorporating a free right ITA versus single ITA + RAs (380 matched pairs), bilateral ITA use demonstrated comparable survival at 15 years (79% ± 4.7% vs 67% ± 5.7%, P = .09). Among patients receiving bilateral ITAs, comparison between in situ right ITA versus free right ITA recipients (206 matched pairs) revealed comparable 15-year survival (84% ± 6.1% vs 79% ± 6.7%, P = .13). Multivariable Cox regression found bilateral ITA use to be protective from mortality (hazard ratio, 0.73; 95% confidence interval, 0.59-0.90, P = .004).The use of bilateral ITAs as an in situ or free conduit is associated with greater survival and seems to offer a prognostic advantage over the use of only a single ITA supplemented by RAs. Therefore, all configurations of TAR are not equivalent.

Postherpetic neuralgia (PHN) is dermatomal distribution pain that persists for months to years after the resolution of herpes zoster rash. The cause of PHN is unknown. Herein, we report clinical, molecular virological, and immunological findings over an 11-year period in an immunocompetent elderly woman with PHN. Initially, blood mononuclear cells (MNCs) contained varicella-zoster virus (VZV) DNA on two consecutive occasions. Random testing after treatment with famciclovir to relieve pain did not detect VZV DNA. However, the patient was reluctant to continue famciclovir indefinitely and voluntarily stopped drug treatment five times. Pain always recurred within 1 week, and blood MNCs contained many, but not all, regions of the VZV genome on all five occasions. Immunological analysis revealed increased cell-mediated immunity to VZV. Chronic VZV ganglionitis-induced PHN best explains the recurrence of VZV DNA in MNCs whenever famciclovir was discontinued; the detection of only some regions of the viral genome in MNCs, compared to the detection of all regions of the VZV genome in latently infected ganglia; the increased cell-mediated immunity to VZV; and a gratifying clinical response to famciclovir. The presence of fragments of VZV DNA in MNCs likely represents partial degradation of viral DNA in MNCs that trafficked through ganglia during productive infection.

Aims To evaluate the relationship between patterns of rosiglitazone use and cardiovascular (CV) outcomes in the Veterans Affairs Diabetes Trial (VADT). Methods Time-dependent survival analyses, case–control and 1 : 1 propensity matching approaches were used to examine the relationship between patterns of rosiglitazone use and CV outcomes in the VADT, a randomized controlled study that assessed the effect of intensive glycaemic control on CV outcomes in 1791 patients with type 2 diabetes (T2D) whose mean age was 60.4 ± 9 years. Participants were recruited between 1 December 2000 and 31 May 2003, and were followed for 5–7.5 years (median 5.6) with a final visit by 31 May 2008. Rosiglitazone (4 mg and 8 mg daily) was initiated per protocol in both the intensive-therapy and standard-therapy groups. Main outcomes included a composite CV outcome, CV death and myocardial infarction (MI). Results Both daily doses of rosiglitazone were associated with lower risk for the primary composite CV outcome [4 mg: hazard ratio (HR) 0.63, 95% confidence interval (CI) 0.49–0.81 and 8 mg: HR 0.60, 95% CI 0.49–0.75] after adjusting for demographic and clinical covariates. A reduction in CV death was also observed (HR 0.25, p

We report a case of an infusion of intra-aortic propofol after the missed inadvertent placement of a centra venous catheter into the right common carotid artery. Radiological imaging revealed bilateral ischaemic infarct in the posterior fossa and right cerebral artery territories consistent with an embolic source. The potential cause of the neurological injuries sustained in this case are explored. Discussion focuses on the sequelae, managemen and prevention of an iatrogenic carotid artery injury from a central venous catheter insertion. Finally, we propose an algorithm for management of iatrogenic carotid artery cannulation.

Background We examined whether socioeconomic status and rurality influenced outcomes after coronary surgery. Methods We identified 14,150 patients undergoing isolated coronary surgery. Socioeconomic and rurality data was obtained from the Australian Bureau of Statistics and linked to patients’ postcodes. Outcomes were compared between categories of socioeconomic disadvantage (highest versus lowest quintiles, n= 3150 vs. 2469) and rurality (major cities vs. remote, n=9598 vs. 839). Results Patients from socioeconomically-disadvantaged areas experienced a greater burden of cardiovascular risk factors including diabetes, obesity and current smoking. Thirty-day mortality (disadvantaged 1.6% vs. advantaged 1.6%, p>0.99) was similar between groups as was late survival (7 years: 83±0.9% vs. 84±1.0%, p=0.79). Those from major cities were less likely to undergo urgent surgery. There was similar 30-day mortality (major cities: 1.6% vs. remote: 1.5%, p=0.89). Patients from major cities experienced improved survival at seven years (84±0.5% vs. 79±2.0%, p=0.010). Propensity-analysis did not show socioeconomic status or rurality to be associated with late outcomes. Conclusion Patients presenting for coronary artery surgery from different socioeconomic and geographic backgrounds exhibit differences in their clinical profile. Patients from more rural and remote areas appear to experience poorer long-term survival, though this may be partially driven by the population's clinical profile.

The pathology of respiratory syncytial virus (RSV) disease in bonnet monkeys parallels findings with human RSV disease. RSV-infected animals pre-immunized with a formalin-inactivated (FI) RSV vaccine develop inflammation in peribronchiolar, perivascular, interstitial and intra-alveolar sites with lung inflammation scores significantly higher than animals with a primary RSV infection and those pre-immunized with an FI-Vero cell control vaccine (P=0·05). Animals previously infected and re-exposed to RSV had significantly lower alveolar, interstitial and total lung inflammation scores than in primary infection (P=0·05). Immunization with two intra-muscular doses of 0·5 ml of the FI-RSV vaccine administered 21 days apart resulted in little serum-neutralizing and ELISA antibody, low levels of secretory IgA and a low lymphocyte proliferative response that was significantly lower than the response observed in animals that were previously infected with live RSV. Higher RSV virus titres were detected in the lungs and lung lavage fluid of monkeys immunized with the FI-RSV vaccine than in those with a primary infection (P=0·001). RSV was detected byin situhybridization in pulmonary inflammatory infiltrates, where the single most abundant infiltrating cellular species was macrophages, so it may be these cells that support the enhanced virus replication that contributes to the enhanced pulmonary pathology of FI-RSV immunization.

Healthy, varicella-zoster virus (VZV)-seropositive subjects, aged 55-89 years (mean age 66 years), received either 4000 PFU of live, attenuated VZV vaccine (n=85) or an equal volume of this vaccine that was heat-inactivated (n=82). Both vaccines significantly boosted VZV antibody (enzyme immunoassay) and gamma-interferon production by peripheral blood mononuclear cells stimulated by VZV antigen. These responses returned to baseline by 12 months. Circulating mononuclear cells that proliferated in response to VZV antigen were significantly more numerous (responder cell frequency assay) after either vaccine, and persisted with a half-life of 17. 5-21.3 months. There were no differences in immune response to either vaccine in this older age cohort.

Estimates of responder cell frequency (RCF) based on limiting dilution analyses are laborious, and alternative means to quantitate cell-mediated immunity to immunogens are desirable. It was shown that levels of interleukin (IL)-2 in the supernatant of varicella-zoster virus-stimulated blood lymphocytes from immune adults peaked at 48 h of culture and correlated partially with estimates of RCF (r = .74, P = .003). Levels of gamma-interferon, IL-4, and IL-10 increased through the first 4 days of culture, and gamma-interferon levels showed some correlation with peak IL-2 levels (r = .48, P = .03). Nevertheless, correlations between levels of these cytokines and RCF did not reach statistically significant levels.

Severe combined immunodeficiency disease (SCID) consists of a group of heterogeneous genetic disorders. The most severe phenotype, T-B- SCID, is inherited as an autosomal recessive trait and is characterized by a profound deficiency of both T cell and B cell immunity. There is a uniquely high frequency of T-B- SCID among Athabascan-speaking Native Americans (A-SCID). To localize the A-SCID gene, we conducted a genomewide search, using linkage analysis of approximately 300 microsatellite markers in 14 affected Athabascan-speaking Native American families. We obtained conclusive evidence for linkage of the A-SCID locus to markers on chromosome 10p. The maximum pairwise LOD scores 4.53 and 4.60 were obtained from two adjacent markers, D10S191 and D10S1653, respectively, at a recombination fraction of straight theta=.00. Recombination events placed the gene in an interval of approximately 6.5 cM flanked by D10S1664 and D10S674. Multipoint analysis positioned the gene for the A-SCID phenotype between D10S191 and D10S1653, with a peak LOD score of 5.10 at D10S191. Strong linkage disequilibrium was found in five linked markers spanning approximately 6.5 cM in the candidate region, suggesting a founder effect with an ancestral mutation that occurred sometime before 1300 A.D.

Selective T cell deficiency is a rare immune deficiency characterized by the absence of CD8 + T lymphocytes and depressed/absent T cell function. This syndrome has been associated with mutations in the gene for ZAP-70, a tyrosine kinase that has profound effects on signaling via the T cell receptor. In this paper we describe a patient with selective T cell deficiency and certain phenotypic features that are unique among the small number of patients described. The patient had virtually absent T cell function, hypogammaglobulinemia, and no response to vaccination. The T lymphocytes failed to respond to mitogenic stimuli, even in the presence of exogenous interleukin 2. Similar to other patients with this disorder, the T cells were capable of proliferating when stimulated by pharmacologic agents such as phorbol ester and ionomycin. While peripheral blood T cells had limited capability to increase cytosolic Ca 2+ levels in response to mitogenic stimulation, thymocytes responded to a large panel of antibodies and mitogens. This report broadens the spectrum of clinical presentations associated with selective T cell deficiency and, for the first time, compares the responses of both peripheral T cells and thymocytes. The data support the concept that the defect in signal transduction resulting from the absence of ZAP-70 is primarily manifested following export of T lymphocytes from the thymus and that selection of CD8-positive T cells is dependent on the presence of ZAP-70.

Several mutations involving the fibroblast growth factor receptor (FGFR) gene family have been identified in association with phenotypically distinct forms of craniosynostosis. One such point mutation, resulting in the substitution of proline by arginine in a critical region of the linker region between the first and second immunoglobulin-like domains, is associated with highly specific phenotypic consequences in that mutation at this point in FGFR1 results in Pfeiffer syndrome and analogous mutation in FGFR2 results in Apert syndrome. We now show that a much more variable clinical presentation accompanies analogous mutation in the FGFR3 gene. Specifically, mental retardation, apparently unrelated to the management of the craniosynostosis, appears to be a variable clinical consequence of this FGFR3 mutation.

We report a case of thrombotic thrombocytopenic purpura in a woman post mitral valve repair who presented with unexplained thrombocytopenia, intermittent fever, acute renal failure and severe digital ischaemia. The diagnosis of thrombotic thrombocytopenic purpura was confirmed after exclusion of many of the aetiological factors of postoperative digital ischaemia, a positive haemolytic screen and blood film examination which showed schistocytes and fragmented red cells. Plasma ADAMTS-13 activity measured by enzyme-linked immunosorbent assay was reduced. Treatment of thrombotic thrombocytopenic purpura with exchange plasmapheresis and methylprednisolone was of paramount importance and the patient was discharged home on day 30 with complete recovery of haematological, neurological and renal function. In order to increase the awareness of this rare multisystem process, we report our experience in managing this life-threatening condition. Our discussion covers the diagnostic challenges, theories on aetiology, pathogenesis and treatment of this condition in the context of cardiac surgery.