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OBJECTIVE: To measure anti-glycan antibodies (AGA) in cervical cancer (CC) patient sera and assess their effect on therapeutic outcome. PATIENTS AND METHODS: Serum AGA was measured in 276 stage II and 292 stage III Peruvian CC patients using a high content and throughput Luminex multiplex glycan array (LMGA) containing 177 glycans. Association with disease-specific survival (DSS) and progression free survival (PFS) were analyzed using Cox regression. RESULTS: AGAs were detected against 50 (28.3%) of the 177 glycans assayed. Of the 568 patients, 84.5% received external beam radiation therapy (EBRT) plus brachytherapy (BT), while 15.5% only received EBRT. For stage-matched patients (Stage III), receiving EBRT alone was significantly associated with worse survival (HR 6.4, p < 0.001). Stage III patients have significantly worse survival than Stage II patients after matching for treatment (HR = 2.8 in EBRT+BT treatment group). Furthermore, better PFS and DSS were observed in patients positive for AGA against multiple glycans belonging to the blood group H, Lewis, Ganglio, Isoglobo, lacto and sialylated tetrarose antigens (best HR = 0.49, best p = 0.0008). CONCLUSIONS: Better PFS and DSS are observed in cervical cancer patients that are positive for specific antiglycan antibodies and received brachytherapy.

Malignant chromophobe renal cancer (chRCC) and benign oncocytoma (RO) are two renal tumor types difficult to differentiate using histology and immunohistochemistry-based methods because of their similarity in appearance. We previously developed a transcriptomics-based classification pipeline with “Chromophobe-Oncocytoma Gene Signature” (COGS) on a single-molecule counting platform. Renal cancer patients (n=32, chRCC=17, RO=15) were recruited from Augusta University Medical Center (AUMC). Formalin-fixed paraffin-embedded (FFPE) blocks from their excised tumors were collected. We created a custom single-molecule counting code set for COGS to assay RNA from FFPE blocks. Utilizing hematoxylin-eosin stain, pathologists were able to correctly classify these tumor types (91.8%). Our unsupervised learning with UMAP (accuracy = 0.97) and hierarchical clustering (accuracy = 1.0) identified two clusters congruent with their histology. We next developed and compared four supervised models (random forest, support vector machine, generalized linear model with L2 regularization, and supervised UMAP). Supervised UMAP has shown to classify all the cases correctly (sensitivity = 1, specificity = 1, accuracy = 1) followed by random forest models (sensitivity = 0.84, specificity = 1, accuracy = 1). This pipeline can be used as a clinical tool by pathologists to differentiate chRCC from RO.Simple SummaryWe previously reported a gene signature, “Chromophobe-Oncocytoma Gene Signature” (COGS), to differentiate Chromophobe renal cell carcinoma from oncocytoma. Here, we report our results on a single-molecule counting assay with machine learning as a diagnostic pipeline to differentiate chromophobe and oncocytoma tumors utilizing the COGS signature to be used in clinics.

Type 1 diabetes (T1D) is an autoimmune disease, characterized by the presence of auto-antibodies to several protein and non-protein antigens. We report circulating levels of antibodies towards naturally occurring glycans using our customized glycan array and show that anti-carbohydrate antibodies (ACA) are associated with pathogenesis and progression to T1D. We compared circulatory levels of ACAs against 202 glycans in a cross-sectional cohort of T1D patients (n=278) and healthy controls (n=298), as well as in a longitudinal cohort (n=112). We identified 11 clusters of ACAs associated with glycan function class. Clusters enriched for aminoglycosides, blood group A and B antigens, glycolipids, ganglio-series, and O-linked glycans were associated with progression to T1D. ACAs against the aminoglycoside commonly used for neonatal sepsis, gentamicin, and its related structures, G418 and sisomicin, were associated with islet autoimmunity. ACAs improved discrimination of T1D status of individuals over a model with only clinical variables. ACAs are potential biomarkers for T1D.

Development of complications in type 1 diabetes patients can be reduced by modifying risk factors. We used a cross-sectional cohort of 1646 patients diagnosed with type 1 diabetes (T1D) to develop a clinical risk score for diabetic peripheral neuropathy (DPN), autonomic neuropathy (AN), retinopathy (DR), and nephropathy (DN). Of these patients, 199 (12.1%) had DPN, 63 (3.8%) had AN, 244 (14.9%) had DR, and 88 (5.4%) had DN. We selected five variables to include in each of the four microvascular complications risk models: age, age of T1D diagnosis, duration of T1D, and average systolic blood pressure and HbA1C over the last three clinic visits. These variables were selected for their strong evidence of association with diabetic complications in the literature and because they are modifiable risk factors. We found the optimism-corrected R2 and Harrell’s C statistic were 0.39 and 0.87 for DPN, 0.24 and 0.86 for AN, 0.49 and 0.91 for DR, and 0.22 and 0.83 for DN, respectively. This tool was built to help inform patients of their current risk of microvascular complications and to motivate patients to control their HbA1c and systolic blood pressure in order to reduce their risk of these complications.

Development of complications in type-1 diabetes patients can be reduced by modifying risk factors. We used a cross-sectional cohort of 1646 patients diagnosed with type 1 diabetes (T1D) to develop a clinical risk score for diabetic peripheral neuropathy (DPN), autonomic neuropathy (AN), retinopathy (DR), and nephropathy (DN). Of these patients, 199 (12.1%) had DPN, 63 (3.8%) had AN, 244 (14.9%) had DR, and 88 (5.4%) had DN. We selected five variables to include in each of the four microvascular complications risk models: age, age of T1D diagnosis, duration of T1D, and average systolic blood pressure and HbA1C over the last three clinic visits. These variables were selected for their strong evidence of association with diabetic complications in the literature and because they are modifiable risk factors. We found the optimism-corrected R2 and Harrell’s C statistic were 0.39 and 0.87 for DPN, 0.24 and 0.86 for AN, 0.49 and 0.91 for DR, and 0.22 and 0.83 for DN respectively.This tool (https://ptran25.shinyapps.io/Diabetic_Peripheral_Neuropathy_Risk) was built to help inform patients of their current risk of microvascular complications and to motivate patients to control their HbA1c and systolic blood pressure in order to reduce their risk of these complications.

Multiple cross-sectional and longitudinal studies have shown that serum levels of the chemokine ligand 2 (CCL-2) are associated with type 1 diabetes (T1D), although the direction of effect differs. We assessed CCL-2 serum levels in a longitudinal cohort to clarify this association, combined with genetic data to elucidate the regulatory role of CCL-2 in T1D pathogenesis. The Diabetes Autoimmunity Study in the Young (DAISY) followed 310 subjects with high risk of developing T1D. Of these, 42 became persistently seropositive for islet autoantibodies but did not develop T1D (non-progressors); 48 did develop T1D (progressors). CCL-2 serum levels among the three study groups were compared using linear mixed models adjusting for age, sex, HLA genotype, and family history of T1D. Summary statistics were obtained from the CCL-2 protein quantitative trait loci (pQTL) and CCR2 expression QTL (eQTL) studies. The T1D fine mapping association data were provided by the Type 1 Diabetes Genetics Consortium (T1DGC). Serum CCL-2 levels were significantly lower in both progressors (p = 0.004) and non-progressors (p = 0.005), compared to controls. Two SNPs (rs1799988 and rs746492) in the 3p21.31 genetic locus, which includes the CCL-2 receptor, CCR2, were associated with increased CCR2 expression (p = 8.2e-5 and 5.2e-5, respectively), decreased CCL-2 serum level (p = 2.41e-9 and 6.21e-9, respectively), and increased risk of T1D (p = 7.9e-5 and 7.9e-5, respectively). The 3p21.31 genetic region is associated with developing T1D through regulatory control of the CCR2/CCL2 immune pathway., Highlights • Serum CCL-2 levels are lower in individuals with islet autoantibodies and type 1 diabetes compared to controls. • Serum CCL-2 levels are associated with the 3p21.31 genetic locus. • The 3p21.31 genetic locus is associated with type 1 diabetes. • The 3p21.31 genetic locus is associated with gene expression of the CCL-2 receptor, CCR2.

Gene expression profiling has been shown to be comparable to other molecular methods for glioma classification. We sought to validate a gene-expression based glioma classification method. Formalin-fixed paraffin embedded tissue and flash frozen tissue collected at the Augusta University (AU) Pathology Department between 2000&ndash, 2019 were identified and 2 mm cores were taken. The RNA was extracted from these cores after deparaffinization and bead homogenization. One hundred sixty-eight genes were evaluated in the RNA samples on the nCounter instrument. Forty-eight gliomas were classified using a supervised learning algorithm trained by using data from The Cancer Genome Atlas. An ensemble of 1000 linear support vector models classified 30 glioma samples into TP1 with classification confidence of 0.99. Glioma patients in TP1 group have a poorer survival (HR (95% CI) = 4.5 (1.3&ndash, 15.4), p = 0.005) with median survival time of 12.1 months, compared to non-TP1 groups. Network analysis revealed that cell cycle genes play an important role in distinguishing TP1 from non-TP1 cases and that these genes may play an important role in glioma survival. This could be a good clinical pipeline for molecular classification of gliomas.

Molecular biomarkers that can predict survival and therapeutic outcome are still lacking for cervical cancer. Here we measured a panel of 19 serum proteins in sera from 565 patients with stage II or III cervical cancer and identified 10 proteins that have an impact on disease specific survival (DSS) (Hazzard&rsquo, s ratio, HR = 1.51&ndash, 2.1). Surprisingly, all ten proteins are implicated in senescence-associated secreted phenotype (SASP), a hallmark of cellular senescence. Machine learning using Ridge regression of these SASP proteins can robustly stratify patients with high SASP, which is associated with poor survival, and patients with low SASP associated with good survival (HR = 3.09&ndash, 4.52). Furthermore, brachytherapy, an effective therapy for cervical cancer, greatly improves survival in SASP-high patients (HR = 3.3, p &lt, 5 &times, 10&minus, 5) but has little impact on survival of SASP-low patients (HR = 1.5, p = 0.31). These results demonstrate that cellular senescence is a major determining factor for survival and therapeutic response in cervical cancer and suggest that senescence reduction therapy may be an efficacious strategy to improve the therapeutic outcome of cervical cancer.

Lung adenocarcinoma is one-half of all lung cancer and the third deadliest cancer in the world. The traditional classification of lung adenocarcinoma involves invasiveness, growth pattern, presence of mucin, and other histological features. However, this classification provides limited prognostic predictability. Molecular profiles based The Cancer genome Atlas lung adenocarcinoma cohort classified the tumors into the terminal respiratory unit (TRU), proximal proliferative (PP), and proximal infiltrative (PI) based on unsupervised classification, which did not address clinical applicability to the classification. Here, we developed an unsupervised classification with Density-based UMAP (DBU), which identified four transcriptomic profiles for lung adenocarcinoma (Transcriptomic profile, TP1-TP4). We identified a gene signature with 299 genes to develop a supervised classifier, called Ensemble Transcriptomic classifier (ETC), to identify these four subgroups within the total cohort. All TP1 is PI. TP2 is 49.0% TFU and 45.0% PP. TP3 is 76.2% PI and 23.8% PP. TP4 is 54.5% TFU and 45.5% PI. TP1 is characterized by neuroendocrine-like features and clusters with large cell neuroendocrine tumors in cluster analysis. TP3 is squamous-like enriched with cell cycle and DNA repair high and worse prognosis and groups with squamous cell carcinoma in cluster analysis. TP2 has high immune cell infiltration, and TP4 showed low mutational burden and low immune cell infiltration. We validated these subgroups identified in the TCGA cohort in a microarray meta-dataset with DBU, ETC. This classification showed four subgroups in lung adenocarcinoma, which shows potential clinical actionable findings. Citation Format: Khaled Bin Satter, Paul MH Tran, Lynn KH Tran, John Nechtman, Nikhil Patel, Bruno Santos, Diane Hopkins, Nagla Abdel Karim, Jin-Xiong She, Sharad B. Purohit. Transcriptomic classification of lung adenocarcinoma identifies a novel subgroup with a poor survival prognosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3496.

Objectives To develop a transcriptomic signature capable of predicting overall survival (OS) for uterine serous carcinoma (USC). Methods RNAseq data for 58 USC patients were obtained from TCGA. Expression of 73 candidate genes was measured for 67 Augusta University (AU) samples using NanoString technology. Results Analysis of the TCGA RNAseq data identified 73 genes that individually predict prognosis for USC patients and an elastic net model with all 73 genes (USC73) distinguishes a good OS group with low USC73 score from a poor OS group with high USC73 score (5-year OS = 83.3% and 13.3% respectively, HR = 40.1; p = 3 × 10−8). This finding was validated in the independent AU cohort (HR = 4.3; p = 0.0004). The poor prognosis group with high USC73 score consists of 37.9% and 32.8% of patients in the TCGA and AU cohort respectively. USC73 score and pathologic stage independently contribute to OS and together provide the best prognostic value. Early stage, low USC73 patients have the best prognosis (5-year OS = 85.1% in the combined dataset), while advanced stage, high USC73 patients have the worst prognosis (5-year OS = 6.4%, HR = 30.5, p = 1.2 × 10−12). Consistent with the observed poor survival, primary cell cultures from high USC73 patients had higher proliferation rate and cell cycle progression; and high USC73 patients had lower rates of complete response to standard therapy. Conclusions The USC73 transcriptomic signature and stage independently predict OS of USC patients and the best prediction is achieved using USC73 and stage. USC73 may also serve as a therapeutic biomarker to guide patient care.

This practice forum report details a standardized improvement process that was created both to improve patient outcomes related to various hospital-acquired infections and to address leadership concerns related to incented quality metrics. A 3-year retrospective review identified common issues to guide future interventions and confirmed that this methodology reduced the rate of recurrent infections across the health care system. Process tool samples are provided.

The majority of the English population lives in suburbs and this is where the impacts of climate change will significantly affect people's domestic lives: heat stress, respiratory problems, flooding, drought, deterioration of green spaces and damage from storms. A recognized need exists to adapt suburbs (homes, gardens and public space) physically to mitigate against further climate change and to adapt to inevitable weather patterns. A number of potential adaptation options, addressing different risks, are identified and tested using a range of methods, including modelling, and workshops with residents and professional and institutional stakeholders. The ‘best’ solutions are those that reduce the climate risk within the context of local adaptive capacity. Solutions are effective, acceptable and feasible given the type of suburb; its location; microclimate; housing type; the climate risk it faces; the socio-economic composition of its residents and their attitudes; resources; and governance conditions. It ...

PurposeThis paper presents new research on the potential pathways for integrated adaptation that could make England's suburbs more resilient to future climate conditions. It focuses on the role of central government, local agencies and householders in making adaptations to the built and natural environment.Design/methodologyThis paper uses evidence from three facilitated workshops run with built environment and policy professionals associated with climate change adaptation in three cities in England: Oxford, Bristol and Stockport. The workshop contributions are presented in relation to the potential role that central government, local agencies and residents could play in adapting suburbs.FindingsCentral government, local agencies and householders form an interconnected network of agents responsible for adaptive action in suburbs. Professional and institutional stakeholders expect central government to take a lead and ensure planning policies and building regulations support effective adaptation. However, those local authorities and agencies that are expected to offer leadership locally do not have the resources to make adaptation happen on the ground. Overall, the stakeholders in this research believe that effective adaptation in suburbs may only happen once householders and government have experienced worsening climatic conditions. This could be a very costly stance in the long term.Originality/valueThis paper provides empirical evidence on how stakeholders engaged in suburban adaptation are making changes now, and on how they envisage change in the future. It reveals clearly the challenges involved in integrating mitigation and adaptation actions and highlight the complexities around implementation on the ground.

Saliva offers a relatively noninvasive method for measuring analytes such as cortisol, holding particular promise for use in pediatric populations on a large scale if a rigorous collection protocol is feasible in diverse settings. The Environmental Determinants of Diabetes in the Young study protocol, conducted in centers in the United States, Sweden, Finland, and Germany, used salivary collection to assess cortisol level as a physiologic marker of stress. Saliva was collected using Sorbettes from subjects at 3.5, 4.5, and 5.5 years of age. Parents collected a morning sample, and staff collected pre- and post-blood draw samples. Feasibility was assessed based on protocol completion, adherence with instructions, factors affecting adherence, and sufficiency of saliva sample for cortisol determination. Collection of saliva samples in a diverse pediatric population is feasible. Establishing non-invasive and acceptable methods for collecting physiological parameters of stress will allow better exploration of determinants of health in this important population.

This paper outlines the conditions for, and challenges of, adapting suburbs in England for climate change. The paper introduces the ‘suburb’ as a spatial setting vulnerable to climate change related threats that have been largely absent from previous adaptation studies. It argues that in terms of the impacts of climate change on the daily lives of the UK’s population suburban neighbourhoods need far more attention. It sets out a typology of English suburbs (including inner-historic suburbs, pre-war garden suburbs, interwar suburbs, social housing suburbs, car suburbs, and medium-high density suburbs), and argues that these suburbs will experience both gradual changes in climate and extreme events. The changes will have impacts on ’place’ and ’people’, and modifications to the physical environment to respond to climate change will need to take place if they are to be sustainable in the future. Modifications can be at different scales: home and/or garden and/or neighbourhood. However, whether or not such modifications to the physical environment will be implemented is a function of the ‘response capacity’ in the suburb: and this is determined partly by the existing physical conditions of the suburb, and partly by economic, governance, knowledge and cultural contexts. The paper describes the conditions that underlie the response capacity in suburbs, and reveals the complexity of attempting to ‘climate proof’ some of the most established and valued parts of the English urban landscape.

Historically, pain has been poorly managed in the pediatric emergency department (ED) (PED), resulting in measurable psychosocial issues both acute and delayed.The aim of the study was to measure the impact of protocolized pain management on patients with painful conditions or undergoing painful procedures in the PED.We performed an analysis before and after the implementation of the protocol, dubbed the "Comfort Zone." Validated, age-appropriate pain scales were performed. Validation (using Cronbach α, confirmatory factor analysis) was followed by comparison of responses between the pre- and posttests collected (χ(2) and Wilcoxon rank sum tests). Pain scores were collected at triage and at discharge. At triage, patients were asked to report pain levels. At discharge, they were asked to report their current pain and recall the level of pain during their stay. At triage, parents were asked to report about their perception of the child's pain. At discharge, they were asked to report about their perception of the child's current pain and recall the level of pain during the stay and during procedures, if done.Five hundred thirty-one patients were enrolled in the preprotocol group; 47% were women with a median age of 5 years (range, 30 days-18 years). Two hundred sixty-three patients were enrolled in the protocol group; 39% were women with a median age of 6 years (range, 30 days-18 years). Patient-recalled pain scores of the ED visit in the protocol group were significantly lower than those of the preprotocol group (Wong-Baker Faces Pain Scale, 5.07-4.01; P.001); yet parent estimates of pain did not show a significant change at any point. Patient assessment of pain at ED discharge did not show a significant change either (Wong-Baker Faces Pain Scale, 1.99-1.56; P = .09). The Faces scale is not well validated for patients younger than 4, so that group had only parental assessment of pain and, consistent with the larger data set, showed no significant pain scale reduction at any point.Protocolized pain management reduces patients' memory of pain during PED visits but may not affect parental memory of perceived pain or parent- and patient-reported pain at discharge.

1Plans are among the most durable products of planning, and as such offer a revealing window into the worlds of the planners of their time. In this paper we set out a methodology for viewing those worlds using critical discourse analysis (CDA). This method focuses on four key textual features of plans: construal of substance, construction of agency, generic structure, and presentation. Together they enable the investigator to go beyond thematic discourses and uncover the institutional, political and ideological role of planning during the time period in which plans are produced. We use this method to interrogate the changing rationalities governing planning in Western Australia (WA) since the Second World War by analysing the four major city plans for Perth, covering a period from 1955 to 2010. This longitudinal analysis suggests that planning in WA mirrors concurrent trends in international planning theory, and highlights the significance of “the plan” as an object of inquiry for revealing the changing n...

The present study was conducted to assess genetic associations for type 1 diabetes (T1D) reported in previous genome-wide association studies (GWAS). A total of 21 previously reported single-nucleotide polymorphisms (SNPs) were genotyped by TaqMan assays in 1434 Caucasian T1D patients and 1864 normal controls from Georgia. Analysis of the samples identified 18 SNPs (PTPN22, INS, IFIH1, SH2B3, ERBB3, CTLA4, C14orf181, CTSH, CLEC16A, CD69, ITPR3, C6orf173, SKAP2, PRKCQ, RNLS, IL27, SIRPG and CTRB2) with putative association.

Deliberative policy-making is an alternative method of generating new planning strategies based on the public deliberation of citizens and stakeholders. Four ideals of deliberative policy-making espoused by deliberative democracy theorists are identified. Using this framework the ‘Dialogue with the City’ process undertaken by the Western Australian Government to develop the Network City spatial planning strategy for the Perth metropolitan region is examined. While this process went further than most towards realising the ideals of deliberative policy-making, the Government was not able to fully achieve the ideals of inclusive decision-making, equitable decision-making, deliberation toward the common good and consensus decision-making. It is most likely that the deliberative approach to policy-making does not represent a new model for governing; rather, these participation techniques constitute a more sophisticated model for involving citizens and stakeholders in planning.

This paper sets out the challenges of adapting suburbs for climate change in the context of the compact city agenda. We argue that while the compact city debate does address mitigating climate change at a strategic level, it does not specifically consider adapting existing suburban areas to cope with anticipated changes. We discuss the possibilities for, and challenges of, suburban adaptation. In terms of the built environment, such challenges include: difficulties retrofitting existing housing stock, the fragmented ownership and management of land and housing, and the slow pace of change in suburban areas. In terms of mobilizing social change to affect adaptation, problems of coordinating multi-actor partnerships, developing political will, generating public acceptance, and encouraging behaviour change are identified. We conclude that suburbs pose unique challenges for realizing transformations, and that the 'sustainable development' and 'climate change' discourses have yet to be fully integrated in the light of potential conflicts between mitigation and adaptation measures.

Communicative planning scholars often claim that forms of participatory planning centred on public deliberation can facilitate more equitable decision-making by overcoming power differentials between citizens and stakeholders. This paper draws upon the communicative planning understanding of Habermasian 'communicative action' in order to evaluate the argument that deliberation removes power differences between participants of participatory processes. A case study of a deliberative plan-making process – the Western Australian government's 'Dialogue with the City' – is undertaken to assess this claim. The author argues that there are both deliberate (avoidable, strategic) and inevitable (unavoidable, unintentional) ways in which power differences can arise between participants of deliberative plan-making. Planners who are charged with the responsibility of moderation may find it difficult to identify and mediate power differences in participatory processes; in fact, they may act to reinforce existing power ...

A retrospective case-control study was performed to determine the risks and outcomes associated with pediatric cardiothoracic surgical site infection. Undergoing more than 1 cardiothoracic operative procedure, having preoperative infection, and undergoing surgery on a Monday were significant risk factors. Cardiothoracic surgical site infection increased hospital and pediatric intensive care unit length of stay. Deep surgical site infection significantly increased mortality.

BACKGROUND & AIMS: It is not clear how intake of gluten during infancy affects subsequent risk of celiac disease. We investigated whether gluten intake before 2 years of age increases risk for celiac disease in genetically susceptible children. METHODS: We performed a case-control study of 436 pairs of children, generated from a database of 2525 children with genetic susceptibility to celiac disease in Sweden, matched for sex, birth year, and HLA genotype from September 2004 and February 2010. Children were screened annually for celiac disease using an assay for tissue transglutaminase autoantibodies (tTGA). Intestinal biopsies were collected from children who tested positive for tTGA to confirm the presence of celiac disease. Gluten intake was calculated from 3-day food records collected when the children were 9, 12, 18 and 24 months old. RESULTS: Breastfeeding duration (median 32 weeks) and age at first introduction to gluten (median 22 weeks) did not differ between cases and tTGA-negative children (controls). At the visit prior to tTGA seroconversion, cases reported a larger intake of gluten (median 4.9 g/day) than controls (median 3.9 g/day) (odds ratio [OR], 1.28; 95% confidence interval [CI], 1.13-1.46; P=.0002). More cases consumed amounts of gluten in the upper 3rd tertile (i.e. >5.0 g/day) before they tested positive for tTGA seroconversion than controls (OR, 2.65; 95% CI, 1.70-4.13; P

Previous studies have attempted to elucidate the potential role of various cytokines and chemokines in human type 1 diabetes (T1D); however, the precise role of these serum proteins in T1D is still controversial and undetermined primarily due to the small sample sizes of the previous studies. We profiled a panel of serum cytokines and chemokines using a large-scale, two-stage study design for the discovery and validation of the serum proteins associated with T1D.The participants were patients with T1D and islet autoantibody-negative control subjects from the Phenome and Genome of Diabetes Autoimmunity study.Thirteen cytokines and chemokines were measured in serum of 4424 subjects using multiplex immunoassays.Using 1378 samples in Stage 1, we found that four of the 13 proteins are significantly lower in patients with T1D than controls (IL8: odds ratio [OR] = 0.40; P = 5.7 × 10(-19); IL-1Ra: OR = 0.42; P = 1.1 × 10(-13); MCP-1: OR = 0.60; P = 6.7 × 10(-9); and MIP-1β: OR = 0.63; P = 4.2 × 10(-7)). Our confirmation data with 3046 samples in Stage 2 further confirmed the significant negative associations of these four proteins with T1D (IL8: OR = 0.43; P = 8.9 × 10(-32); IL-1Ra: OR = 0.56, P = 3.7 × 10(-27); MCP-1: OR = 0.61, P = 4.3 × 10(-17); and MIP-1β: OR = 0.69, P = 2.4 × 10(-13)). Quartile analyses also suggested that significantly more T1D cases have protein levels in the bottom quartile than in the top quartile for all four proteins: IL8 (OR = 0.09), IL-1Ra (OR = 0.18), MCP-1 (OR = 0.38), and MIP-1β (OR = 0.44). Furthermore, the negative associations between T1D and serum levels of all four proteins are stronger in genetically high-risk groups compared with the moderate and low-risk groups.IL8, IL-1Ra, MCP-1, and MIP-1β are significantly lower in patients with T1D than controls.

Previous studies have suggested more than 20 genetic intervals that are associated with susceptibility to type 1 diabetes (T1D), but identification of specific genes has been challenging and largely limited to known candidate genes. Here, we report evidence for an association between T1D and multiple single-nucleotide polymorphisms in 197 kb of genomic DNA in the IDDM5 interval. We cloned a new gene (SUMO4), encoding small ubiquitin-like modifier 4 protein, in the interval. A substitution (M55V) at an evolutionarily conserved residue of the crucial CUE domain of SUMO4 was strongly associated with T1D (P = 1.9 x 10(-7)). SUMO4 conjugates to I kappa B alpha and negatively regulates NF kappa B transcriptional activity. The M55V substitution resulted in 5.5 times greater NF kappa B transcriptional activity and approximately 2 times greater expression of IL12B, an NF kappa B-dependent gene. These findings suggest a new pathway that may be implicated in the pathogenesis of T1D.

Methods: We examined monocyte prostaglandin synthase 2 (PGS2/COX2) expression in individuals at risk for or with type 1 diabetes including: (i) 58 established type 1 and 2 diabetic patients; (ii) 34 autoantibody positive (AA+) children and adults; (iii) 164 infants and young children with insulin-dependent diabetes mellitus (IDDM) susceptibility human leukocyte antigen (HLA) alleles; and (iv) 37 healthy control individuals, over a 5-yr period. Results: Established type 1 diabetic patients (1 month to 30+ yr post-disease onset) had significantly higher PGS2 expression than healthy controls; by contrast, insulin-treated type 2 diabetic patients had significantly lower PGS2 expression than healthy controls. Longitudinal studies of AA+ subjects at risk for type 1 diabetes indicated that 73% (11/15) of individuals who developed this disease during the study period expressed high levels of PGS2 prior to or after onset. We also found high level PGS2 expression in genetically at-risk infants and young children that correlated with having a first-degree relative with type 1 diabetes, but not with age, gender, or HLA genotype. In this population, high level PGS2 expression coincided with or preceded autoantibody detection in 30% (3/10) of subjects. Conclusions: These findings suggest that high level monocyte PGS2 expression, although subject to fluctuation, is present in at-risk subjects at an early age and is maintained during progression to and after type 1 diabetes onset.

Objective: We sought to determine risk factors for deep and superficial chest wound infections after coronary artery bypass graft surgery to develop predictive models. Methods: We retrospectively analyzed data collected on 1980 consecutive patients undergoing coronary artery bypass surgery at our institution between January 1, 1996, and June 30, 1999, by using the Society of Thoracic Surgery database. Independent risk factors for surgical-site infection were identified with multivariate logistic regression. Results: There were 37 (1.9%) deep chest and 46 (2.3%) superficial chest surgical-site infections. Obese diabetic patients had a 7.7-fold increased risk of deep chest infections after controlling for intra-aortic balloon pump use (odds ratio, 3.1) and postoperative transfusion (odds ratio, 2.3). Independent risk factors for superficial surgical-site infections included obesity (odds ratio, 3.1), diabetes in persons 65 years of age or older (odds ratio, 2.7), and current smoking (odds ratio, 2.5). Use of antiplatelet drugs was associated with a lower risk of superficial infections (odds ratio, 0.4). Predicted operative mortality as a marker of severity of illness was not clearly predictive of deep or superficial surgical-site infection. Mortality in the year after the operation was increased in patients with deep chest infections compared with that seen in uninfected control subjects (8/37 [21.6%] vs 114/1612 [7.1%], P =.004) but not in patients with superficial chest infections (7/47 [15.2%] vs 114/1612 [7.1%], P =.075). Conclusions: Risk factors for deep and superficial chest surgical-site infections after coronary artery bypass surgery differ, suggesting different mechanisms of pathogenesis. Appropriate risk stratification models specific to these important outcomes must be developed. J Thorac Cardiovasc Surg 2002;124:136-45

Polymorphic markers within the CTLA4 gene on chromosome 2q33 have been shown to be associated with type 1 diabetes. Therefore, a gene responsible for the disease (IDDM12) most likely lies within a region of

The yeast α-1,3-mannosyltransferase (Mnn1p) is localized to the Golgi by independent transmembrane and lumenal domain signals. The lumenal domain is localized to the Golgi complex when expressed as a soluble form (Mnn1-s) by exchange of its transmembrane domain for a cleavable signal sequence (Graham, T. R., and V. A. Krasnov. 1995. Mol. Biol. Cell . 6:809–824). Mutants that failed to retain the lumenal domain in the Golgi complex, called lumenal domain retention ( ldr ) mutants, were isolated by screening mutagenized yeast colonies for those that secreted Mnn1-s. Two genes were identified by this screen, HOG1 , a gene encoding a mitogen-activated protein kinase (MAPK) that functions in the high osmolarity glycerol (HOG) pathway, and LDR1 . We have found that basal signaling through the HOG pathway is required to localize Mnn1-s to the Golgi in standard osmotic conditions. Mutations in HOG1 and LDR1 also perturb localization of intact Mnn1p, resulting in its loss from early Golgi compartments and a concomitant increase of Mnn1p in later Golgi compartments.

There is tremendous scientific and clinical value to further improving the predictive power of autoantibodies because autoantibody-positive (AbP) children have heterogeneous rates of progression to clinical diabetes. This study explored the potential of gene expression profiles as biomarkers for risk stratification among 104 AbP subjects from the Diabetes Autoimmunity Study in the Young (DAISY) using a discovery data set based on microarray and a validation data set based on real-time RT-PCR. The microarray data identified 454 candidate genes with expression levels associated with various type 1 diabetes (T1D) progression rates. RT-PCR analyses of the top-27 candidate genes confirmed 5 genes (BACH2, IGLL3, EIF3A, CDC20, and TXNDC5) associated with differential progression and implicated in lymphocyte activation and function. Multivariate analyses of these five genes in the discovery and validation data sets identified and confirmed four multigene models (BI, ICE, BICE, and BITE, with each letter representing a gene) that consistently stratify high- and low-risk subsets of AbP subjects with hazard ratios >6 (P < 0.01). The results suggest that these genes may be involved in T1D pathogenesis and potentially serve as excellent gene expression biomarkers to predict the risk of progression to clinical diabetes for AbP subjects.

The pathogenic mechanisms underlying Batten disease are unclear. Patients uniformly possess autoantibodies against glutamic acid decarboxylase (GAD) that are predominantly reactive with a region of GAD (amino acids 1 to 20) distinct from subjects with autoimmune type 1 diabetes or stiff-person syndrome. Batten patients did not possess autoantibodies against other type 1 diabetes-associated autoantigens and human leukocyte antigen genotypes revealed no specific associations with this disease.

OBJECTIVE Our previous gene expression microarray studies identified a number of genes differentially expressed in patients with type 1 diabetes (T1D) and islet autoantibody-positive subjects. This study was designed to validate these gene expression changes in T1D patients and to identify gene expression changes in diabetes complications. RESEARCH DESIGH AND METHODS We performed high-throughput real-time RT-PCR to validate gene expression changes in peripheral blood mononuclear cells (PBMCs) from a large sample set of 928 T1D patients and 922 control subjects. RESULTS Of the 18 genes analyzed here, eight genes (S100A8, S100A9, MNDA, SELL, TGFB1, PSMB3, CD74, and IL12A) had higher expression and three genes (GNLY, PSMA4, and SMAD7) had lower expression in T1D patients compared with control subjects, indicating that genes involved in inflammation, immune regulation, and antigen processing and presentation are significantly altered in PBMCs from T1D patients. Furthermore, one adhesion molecule (SELL) and three inflammatory genes mainly expressed by myeloid cells (S100A8, S100A9, and MNDA) were significantly higher in T1D patients with complications (odds ratio [OR] 1.3–2.6, adjusted P value = 0.005–10−8), especially those patients with neuropathy (OR 4.8–7.9, adjusted P value CONCLUSIONS These findings suggest that inflammatory mediators secreted mainly by myeloid cells are implicated in T1D and its complications.

LESSON LEARNED: There are many different causes of delay in recognition and appropriate treatment for sepsis patients. Utilizing RPI methodology assists organizations in finding their specific causes and implement targeted solutions to make a significant patient impact. By using a multidisciplinary team approach, members were challenged to design tools aimed at alleviating process breakdown and creating new practices for better outcomes; ultimately this resulted in increased awareness of the disease process and ultimately reduced mortality.

Genome-wide association (GWA) studies revealed a number of single nucleotide polymorphisms (SNPs) significantly associated with type 1 diabetes (T1D). In an attempt to confirm some of these candidate associations, we genotyped 2046 Caucasian patients and 2417 normal controls from the United States for SNPs in five genomic regions. While no evidence was obtained for four genomic regions (rs2929366/NM_144715 on chromosome 3, rs9127/Q7Z4C4 on chromosome 5, rs1445898/CAPSL on chromosome 5 and rs2302188/NM_033543 on chromosome 19), we provide strong evidence for association between T1D and multiple SNPs in the IFIH1 linkage disequilibrium (LD) block on chromosome 2q. Among the 10 SNPs genotyped for the 2q region, four SNPs located within the IFIH1 gene or at the 5' region of IFIH1 showed significant association with T1D in the Georgia population [odds ratio (OR) = 1.7-1.9] with the best P-value found at SNP rs1990760 (P = 8 x 10(-8) and OR = 1.9). Several SNPs outside of the IFIH1 gene also showed significant but weaker associations. Furthermore, IFIH1 gene expression levels in peripheral blood mononuclear cells are significantly correlated with IFIH1 genotypes, and higher IFIH1 levels are found in individuals with the susceptible genotypes (P = 0.005). Thus, both genetic association and gene expression data suggest that IFIH1 is the most plausible candidate gene implicated in T1D in this LD block.

Dendritic cells uniquely orchestrate the delicate balance between T cell immunity and regulation and an imbalance favoring immunogenic rather than tolerogenic DC is believed to contribute to the development of autoimmune diseases such as type 1 diabetes (T1D). In this study, we determined the frequencies of three blood DC subsets (pDC, mDC1 and mDC2) in 72 T1D patients and 75 normal controls using the Miltenyi blood DC enumeration kit. The frequency of blood pDC was found to be negatively correlated with subject age in both normal controls and T1D patients ( p = 0.0007), while the frequency of mDC1 and mDC2 do not change significantly with subject age. More importantly, the mean frequency of pDC in blood was, after adjusting for age, significantly lower in T1D (mean = 0.127%) than controls (mean = 0.188%) ( p − 5 ), whereas no difference was observed for mDC1 and mDC2 between T1D and controls. Furthermore, T1D patients have a lower proportion of pDC and higher proportion of mDC1 among the total blood DC population than normal controls. These results indicate that the frequency of blood pDC and the pDC/mDC1 ratio are negatively associated with T1D.