Voice Synthesis Improvement by Machine Learning of Natural Prosody.

Since the advent of modern computing, researchers have striven to make the human-computer interface (HCI) as seamless as possible. Progress has been made on various fronts, e.g., the desktop metaphor (interface design) and natural language processing (input). One area receiving attention recently is voice activation and its corollary, computer-generated speech. Despite decades of research and development, most computer-generated voices remain easily identifiable as non-human. Prosody in speech has two primary components-intonation and rhythm-both often lacking in computer-generated voices. This research aims to enhance computer-generated text-to-speech algorithms by incorporating melodic and prosodic elements of human speech. This study explores a novel approach to add prosody by using machine learning, specifically an LSTM neural network, to add paralinguistic elements to a recorded or generated voice. The aim is to increase the realism of computer-generated text-to-speech algorithms, to enhance electronic reading applications, and improved artificial voices for those in need of artificial assistance to speak. A computer that is able to also convey meaning with a spoken audible announcement will also improve human-to-computer interactions. Applications for the use of such an algorithm may include improving high-definition audio codecs for telephony, renewing old recordings, and lowering barriers to the utilization of computing. This research deployed a prototype modular platform for digital speech improvement by analyzing and generalizing algorithms into a modular system through laboratory experiments to optimize combinations and performance in edge cases. The results were encouraging, with the LSTM-based encoder able to produce realistic speech. Further work will involve optimizing the algorithm and comparing its performance against other approaches.

The common drivers of children and young people's health and wellbeing across 13 local government areas: a systems view.

BACKGROUND: System dynamics approaches, including group model building (GMB) and causal loop diagrams (CLDs), can be used to document complex public health problems from a community perspective. This paper aims to apply Social Network Analysis (SNA) methods to combine multiple CLDs created by local communities into a summary CLD, to identify common drivers of the health and wellbeing of children and young people. METHODS: Thirteen community CLDs regarding children and young people health and wellbeing were merged into one diagram involving three steps: (1) combining variable names; (2) CLD merging, where multiple CLDs were combined into one CLD with a set of unique variables and connections; (3) paring, where the Decision-Making Trial and Evaluation Laboratory (DEMATEL) method was used to generate a cut-point to reduce the number of variables and connections and to rank the overall importance of each variable in the merged CLD. RESULTS: Combining variable names resulted in 290 variables across the 13 CLDS. A total of 1,042 causal links were identified in the merged CLD. The DEMATEL analysis of the merged CLD identified 23 common variables with a net importance between 1.0 and 4.5 R + C values and 57 causal links. The variables with the highest net importance were 'mental health' and 'social connection & support' classified as high net receivers of influence within the system. CONCLUSIONS: Combining large CLDs into a simple diagram represents a generalisable model of the drivers of complex health problems.

Examination of Traditional Botnet Detection on IoT-Based Bots.

A botnet is a collection of Internet-connected computers that have been suborned and are controlled externally for malicious purposes. Concomitant with the growth of the Internet of Things (IoT), botnets have been expanding to use IoT devices as their attack vectors. IoT devices utilise specific protocols and network topologies distinct from conventional computers that may render detection techniques ineffective on compromised IoT devices. This paper describes experiments involving the acquisition of several traditional botnet detection techniques, BotMiner, BotProbe, and BotHunter, to evaluate their capabilities when applied to IoT-based botnets. Multiple simulation environments, using internally developed network traffic generation software, were created to test these techniques on traditional and IoT-based networks, with multiple scenarios differentiated by the total number of hosts, the total number of infected hosts, the botnet command and control (CnC) type, and the presence of aberrant activity. Externally acquired datasets were also used to further test and validate the capabilities of each botnet detection technique. The results indicated, contrary to expectations, that BotMiner and BotProbe were able to detect IoT-based botnets-though they exhibited certain limitations specific to their operation. The results show that traditional botnet detection techniques are capable of detecting IoT-based botnets and that the different techniques may offer capabilities that complement one another.

Inhibition of selenoprotein synthesis is not the mechanism by which auranofin inhibits growth of Clostridioides difficile.

Clostridioides difficile infections (CDIs) are responsible for a significant number of antibiotic-associated diarrheal cases. The standard-of-care antibiotics for C. difficile are limited to fidaxomicin and vancomycin, with the recently obsolete metronidazole recommended if both are unavailable. No new antimicrobials have been approved for CDI since fidaxomicin in 2011, despite varying rates of treatment failure among all standard-of-care drugs. Drug repurposing is a rational strategy to generate new antimicrobials out of existing therapeutics approved for other indications. Auranofin is a gold-containing anti-rheumatic drug with antimicrobial activity against C. difficile and other microbes. In a previous report, our group hypothesized that inhibition of selenoprotein biosynthesis was auranofin's primary mechanism of action against C. difficile. However, in this study, we discovered that C. difficile mutants lacking selenoproteins are still just as sensitive to auranofin as their respective wild-type strains. Moreover, we found that selenite supplementation dampens the activity of auranofin against C. difficile regardless of the presence of selenoproteins, suggesting that selenite's neutralization of auranofin is not because of compensation for a chemically induced selenium deficiency. Our results clarify the findings of our original study and may aid drug repurposing efforts in discovering the compound's true mechanism of action against C. difficile.

Evaluation of Derivatives of (+)-Puupehenone against Clostridioides difficile and Other Gram-Positive Bacteria.

Patients receiving healthcare are at higher risk of acquiring healthcare-associated infections, which cause a significant number of illnesses and deaths. Most pathogens responsible for these infections are highly resistant to multiple antibiotics, prompting the need for discovery of new therapeutics to combat these evolved threats. We synthesized structural derivatives of (+)-puupehenone, a marine natural product, and observed growth inhibition of several clinically relevant Gram-positive bacteria, particularly Clostridioides difficile. The most potent compounds-(+)-puupehenone, 1, 15, 19, and 20-all inhibited C. difficile in the range of 2.0-4.0 µg/mL. Additionally, when present in the range of 1-8 µg/mL, a subset of active compounds-(+)-puupehenone, 1, 6, 15, and 20-greatly reduced the ability of C. difficile to produce exotoxins, which are required for disease in infected hosts. Our findings showcase a promising class of compounds for potential drug development against Gram-positive pathogens, such as C. difficile.

d-Proline Reductase Underlies Proline-Dependent Growth of Clostridioides difficile.

Clostridioides difficile is a nosocomial pathogen that colonizes the gut and causes diarrhea, colitis, and severe inflammation. Recently, C. difficile has been shown to use toxin-mediated inflammation to promote host collagen degradation, which releases several amino acids into the environment. Amino acids act as electron donors and acceptors in Stickland metabolism, an anaerobic process involving redox reactions between pairs of amino acids. Proline, glycine, and hydroxyproline are the three main constituents of collagen and are assumed to act as electron acceptors, but their exact effects on the growth and physiology of C. difficile are still unclear. Using three standard culture media (supplemented brain heart infusion [BHIS], tryptone-yeast [TY], and C. difficile minimal medium [CDMM]) supplemented with proline, glycine, or hydroxyproline, we grew C. difficile strains R20291, JIR8094, and a panel of mutants unable to express the Stickland selenoenzymes d-proline reductase and glycine reductase. In the wild-type strains, growth yields in rich media (BHIS and TY) were higher with proline and hydroxyproline but not glycine; moreover, proline-stimulated growth yields required the activity of d-proline reductase, whereas hydroxyproline-stimulated growth yields were independent of its activity. While assumed to be a proline auxotroph, C. difficile could surprisingly grow in a defined medium (CDMM) without proline but only if d-proline reductase was absent. We believe the mere presence of this enzyme ultimately determines the organism's strict dependence on proline and likely defines the bioenergetic priorities for thriving in the host. Finally, we demonstrated that addition of proline and hydroxyproline to the culture medium could reduce toxin production but not in cells lacking selenoproteins. IMPORTANCE Stickland metabolism is a core facet of C. difficile physiology that likely plays a major role in host colonization. Here, we carefully delineate the effects of each amino acid on the growth of C. difficile with respect to the selenoenzymes d-proline reductase and glycine reductase. Moreover, we report that d-proline reductase forces C. difficile to strictly depend on proline for growth. Finally, we provide evidence that proline and hydroxyproline suppress toxin production and that selenoproteins are involved in this mechanism. Our findings highlight the significance of selenium-dependent Stickland reactions and may provide insight on what occurs during host infection, especially as it relates to the decision to colonize based on proline as a nutrient.

The impact of coalition characteristics on outcomes in community-based initiatives targeting the social determinants of health: a systematic review.

BACKGROUND: Coalitions are a popular mechanism for delivering community-based health promotion. The aim of this systematic review was to synthesize research that has quantitatively analyzed the association between coalition characteristics and outcomes in community-based initiatives targeting the social determinants of health. Coalition characteristics described elements of their structure or functioning, and outcomes referred to both proximal and distal community changes. METHODS: Authors searched six electronic databases to identify peer reviewed, published studies that analyzed the relationship between coalition characteristics and outcomes in community-based initiatives between 1980 and 2021. Studies were included if they were published in English and quantitatively analyzed the link between coalition characteristics and outcomes. Included studies were assessed for quality using the Joanna Briggs Institute analytical cross-sectional studies assessment tool. RESULTS: The search returned 10,030 unique records. After screening, 26 studies were included from six countries. Initiatives targeted drug use, health equity, nutrition, physical activity, child and youth development, crime, domestic violence, and neighbourhood improvement. Community outcomes measured included perceived effectiveness (n=10), policy, systems or environment change (n=9), and community readiness or capacity (n=7). Analyses included regression or correlation analysis (n=16) and structural equation or pathway modelling (n=10). Studies varied in quality, with a lack of data collection tool validation presenting the most prominent limitation to study quality. Statistically significant associations were noted between community outcomes and wide range of coalition characteristics, including community context, resourcing, coalition structure, member characteristics, engagement, satisfaction, group facilitation, communication, group dynamics, relationships, community partnership, and health promotion planning and implementation. CONCLUSION: Existing literature demonstrates that coalition characteristics, including best practice health promotion planning and evaluation, influence community outcomes. The field of coalition research would benefit from more consistent description and measurement of coalition characteristics and outcomes, and efforts to evaluate coalitions in a wider range of countries around the world. Further research using empirical community outcome indicators, and methods that consider the interrelationship of variables, is warranted. TRIAL REGISTRATION: A protocol for this review was registered with PROSPERO ( CRD42020205988 ).

Use of artificial intelligence to enable dark nudges by transnational food and beverage companies: analysis of company documents.

OBJECTIVE: To describe the use of artificial intelligence (AI)-enabled dark nudges by leading global food and beverage companies to influence consumer behaviour. DESIGN: The five most recent annual reports (ranging from 2014-2018 or 2015-2019, depending on the company) and websites from 12 of the leading companies in the global food and beverage industry were reviewed to identify uses of AI and emerging technologies to influence consumer behaviour. Uses of AI and emerging technologies were categorised according to the Typology of Interventions in Proximal Physical Micro-Environments (TIPPME) framework, a tool for categorising and describing nudge-type behaviour change interventions (which has also previously been used to describe dark nudge-type approaches used by the alcohol industry). SETTING: Not applicable. PARTICIPANTS: 12 leading companies in the global food and beverage industry. RESULTS: Text was extracted from 56 documents from 11 companies. AI-enabled dark nudges used by food and beverage companies included those that altered products and objects' availability (e.g., social listening to inform product development), position (e.g., decision technology and facial recognition to manipulate the position of products on menu boards), functionality (e.g., decision technology to prompt further purchases based on current selections) and presentation (e.g., augmented or virtual reality to deliver engaging and immersive marketing). CONCLUSIONS: Public health practitioners and policymakers must understand and engage with these technologies and tactics if they are to counter industry promotion of products harmful to health, particularly as investment by the industry in AI and other emerging technologies suggests their use will continue to grow.

Participatory research with a rural Aboriginal Community Controlled Health Organisation: lessons learned using the CONSIDER statement.

CONTEXT: In Australia, Aboriginal Community Controlled Health Organisations (ACCHOs) are geographically proximal to where Aboriginal and Torres Strait Islander People reside and are valued for providing holistic and culturally safe primary health care. Partnering with ACCHOs in research is appropriate for redressing health inequities experienced by Aboriginal and Torres Strait Islander People, which includes a high burden of chronic disease. Historically, some approaches to Aboriginal and Torres Strait Islander health research have been unethical. Greater accountability in the research process, transparency in reporting, and use of culturally appropriate research methodologies are key recommendations to improving the ethical integrity of research. The need for strengthening the reporting of health research involving Aboriginal and Torres Strait Islander People and Indigenous peoples globally led to the development of the CONSolIDated critERia for strengthening the reporting of health research involving Indigenous peoples (CONSIDER statement), which is a synthesis of international ethical guidelines. This project report uses the CONSIDER statement to critically reflect on participatory research undertaken in partnership with an ACCHO in the rural context and to identify lessons of value for future research. ISSUE: By using the CONSIDER statement as a tool for critical reflection, it was identified that processes used to establish a research partnership with an ACCHO were key to setting the research agenda, including identifying ethical issues, the needs of local Aboriginal and Torres Strait Islander People, and expectations from the research. The participation of Aboriginal community members throughout the entire research process was not only methodologically important but was also ethically appropriate. Research activities in this project included opportunities for Aboriginal community members to directly share their perspectives and experiences and develop local solutions to issues affecting them. Outcomes included evidence to support future funding applications, community-derived priorities that assisted with government reporting, and locally identified methods for addressing chronic disease management. Key to this was building the research capacity and capability of local Aboriginal community members, which also reflected the ethical principles of reciprocity and equity. This also provided opportunities for non-Indigenous researchers to learn from local Aboriginal community members and develop skills in culturally appropriate research. LESSONS LEARNED: Using the CONSIDER statement was beneficial in enabling researchers to critically reflect on a participatory research project undertaken in partnership with a rural ACCHO. Researchers identified that participatory approaches can be used to generate research of relevance to local Aboriginal community members and their ACCHOs, and to support health service reporting, and future funding applications. Research timelines and activities needed to be flexible and adaptable, to allow for staff turnover and unforeseen events of cultural significance. Similarly, it is important for researchers to be receptive to change and open to learning. Although research partnerships are established on trust and mutual respect, it is recommended that greater formal provisions are required to protect the intellectual property of Aboriginal and Torres Strait Islander communities involved in research. These lessons are likely to be transferrable to other settings and are of value to researchers seeking to partner with ACCHOs in research.

Silent embolism of a large thrombus in transit through the patent foramen ovale: a case report.

BACKGROUND: Detection of a thrombus in transit through a patent foramen ovale (PFO) is extremely rare due to the transient nature of the process. We report an unusual case of a large, paradoxical embolus in transit seen on echocardiography through a PFO that was not found upon atriotomy. CASE SUMMARY: An 80-year-old woman presented to the emergency room with shortness of breath and right leg pain. She was haemodynamically stable on presentation, and her physical exam was unremarkable. An ultrasound of her right leg revealed a deep vein thrombus in the posterior tibial vein, and chest computed tomography angiography showed saddle pulmonary emboli. Transthoracic echocardiogram identified a large thrombus in transit through a PFO, which was confirmed with a transoesophageal echocardiogram (TOE). She underwent an emergency embolectomy. The thrombus in transit was confirmed by TOE prior to bypass initiation; however, no thrombi were found in any chambers of the heart following atriotomy. Her postoperative recovery was uneventful. She had no focal neurological deficits or any apparent signs of large vessel embolization. DISCUSSION: Cases of silent embolism have been reported in the literature, although they are rare. To our knowledge, this is the first case of a large thrombus in transit through a PFO in an elderly female that was confirmed by an intra-operative TOE but could not be found following atriotomy, with no obvious clinical signs of embolization.

Tracking implementation within a community-led whole of system approach to address childhood overweight and obesity in south west Sydney, Australia.

BACKGROUND: Obesity is a chronic disease that contributes to additional comorbidities including diabetes, kidney disease and several cancers. Change4Campbelltown implemented a 'whole of system' approach to address childhood overweight and obesity. We present methods to track implementation and stakeholder engagement in Change4Campbelltown. METHODS: Change4Campbelltown aimed to build capacity among key leaders and the broader community to apply techniques from systems thinking to develop community-led actions that address childhood obesity. Change4Campbelltown comprised development of a stakeholder-informed Causal Loop Diagram (CLD) and locally-tailored action plan, formation of key stakeholder and community working groups to prioritise and implement actions, and continuous monitoring of intervention actions. Implementation data included an action register, stakeholder engagement database and key engagement activities and were collected quarterly by the project management team over 2 years of reporting. RESULTS: Engagement activities increased level of community engagement amongst key leaders, the school-sector and community members. Community-led action increased as engagement increased and this action is mapped directly to the primary point of influence on the CLD. As action spread diversified across the CLD, the geographical spread of action within the community increased. CONCLUSIONS: This paper provides a pragmatic example of the methods used to track implementation of complex interventions that are addressing childhood overweight and obesity.

Exploring the selenium-over-sulfur substrate specificity and kinetics of a bacterial selenocysteine lyase.

Selenium is a vital micronutrient in many organisms. While traces are required for microbial utilization, excess amounts are toxic; thus, selenium can be regarded as a biological double-edged sword. Selenium is chemically similar to the essential element sulfur, but curiously, evolution has selected the former over the latter for a subset of oxidoreductases. Enzymes involved in sulfur metabolism are less discriminate in terms of preventing selenium incorporation; however, its specific incorporation into selenoproteins reveals a highly discriminate process that is not completely understood. We have identified SclA, a NifS-like protein in the nosocomial pathogen, Enterococcus faecalis, and characterized its enzymatic activity and specificity for l-selenocysteine over l-cysteine. It is known that Asp-146 is required for selenocysteine specificity in the human selenocysteine lyase. Thus, using computational biology, we compared the bacterial and mammalian enzymes and identified His-100, an Asp-146 ortholog in SclA, and generated site-directed mutants in order to study the residue's potential role in the l-selenocysteine discrimination mechanism. The proteins were overexpressed, purified, and characterized for their biochemical properties. All mutants exhibited varying Michaelis-Menten behavior towards l-selenocysteine, but His-100 was not found to be essential for this activity. Additionally, l-cysteine acted as a competitive inhibitor of all enzymes with higher affinity than l-selenocysteine. Finally, we discovered that SclA exhibited low activity with l-cysteine as a poor substrate regardless of mutations. We conclude that His-100 is not required for l-selenocysteine specificity, underscoring the inherent differences in discriminatory mechanisms between bacterial NifS-like proteins and mammalian selenocysteine lyases.

Right and Left-Sided Carcinoid Heart Disease in the Setting of Selective Serotonin Reuptake Inhibitor Use.

Carcinoid heart disease is a complication of carcinoid syndrome. The role of selective serotonin reuptake inhibitors in carcinoid heart disease is unclear. We present a case of refractory heart failure due to right- and left-sided carcinoid heart disease in the setting of selective serotonin reuptake inhibitor use despite remission of carcinoid syndrome. (Level of Difficulty: Beginner.).

Native valve Neisseria meningitidis endocarditis with embolic infarcts.

Infective endocarditis caused by Neisseria meningitidis (NM) is a very rare manifestation of invasive meningococcal disease with only a few cases described in the literature. We report a case of a native mitral valve endocarditis caused by NM in a 61-year-old female without meningitis. Our case highlights the importance of considering NM as one of the causative organisms of infective endocarditis, even in the absence of meningitis. Even though the cases of NM endocarditis have drastically decreased with the advent of antibacterials, NM should always be considered in the differential diagnosis in certain high-risk groups, like diabetics, polysubstance abusers, and elderly individuals. The prognosis is good with early appropriate antibiotic treatment with or without surgery.

Tools and analytic techniques to synthesise community knowledge in CBPR using computer-mediated participatory system modelling.

Participatory systems thinking methods are often used in community-based participatory research to engage and respond to complexity. Participation in systems thinking activities creates opportunities for participants to gain useful insights about complexity. It is desirable to design activities that extend the benefits of this participation into communities, as these insights are predictive of success in community-based prevention. This study tests an online, computer-mediated participatory system modelling platform (STICKE) and associated methods for collating and analysing its outputs. STICKE was trialled among a group of community members to test a computer-mediated system modelling exercise. The causal diagrams resulting from the exercise were then merged, and network analysis and DEMATEL methods applied to inform the generation of a smaller summary model to communicate insights from the participant group as a whole. Participants successfully completed the online modelling activity, and created causal diagrams consistent with expectations. The DEMATEL analysis was identified as the participant-preferred method for converging individuals causal diagrams into a coherent and useful summary. STICKE is an accessible tool that enabled participants to create causal diagrams online. Methods trialled in this study provide a protocol for combining and summarising individual causal diagrams that was perceived to be useful by the participant group. STICKE supports communities to consider and respond to complex problems at a local level, which is cornerstone of sustainable effective prevention. Understanding how communities perceive their own health challenges will be important to better support and inform locally owned prevention efforts.

A Cancelable Iris- and Steganography-Based User Authentication System for the Internet of Things.

Remote user authentication for Internet of Things (IoT) devices is critical to IoT security, as it helps prevent unauthorized access to IoT networks. Biometrics is an appealing authentication technique due to its advantages over traditional password-based authentication. However, the protection of biometric data itself is also important, as original biometric data cannot be replaced or reissued if compromised. In this paper, we propose a cancelable iris- and steganography-based user authentication system to provide user authentication and secure the original iris data. Most of the existing cancelable iris biometric systems need a user-specific key to guide feature transformation, e.g., permutation or random projection, which is also known as key-dependent transformation. One issue associated with key-dependent transformations is that if the user-specific key is compromised, some useful information can be leaked and exploited by adversaries to restore the original iris feature data. To mitigate this risk, the proposed scheme enhances system security by integrating an effective information-hiding technique-steganography. By concealing the user-specific key, the threat of key exposure-related attacks, e.g., attacks via record multiplicity, can be defused, thus heightening the overall system security and complementing the protection offered by cancelable biometric techniques.

Quantifying a Systems Map: Network Analysis of a Childhood Obesity Causal Loop Diagram.

Causal loop diagrams developed by groups capture a shared understanding of complex problems and provide a visual tool to guide interventions. This paper explores the application of network analytic methods as a new way to gain quantitative insight into the structure of an obesity causal loop diagram to inform intervention design. Identification of the structural features of causal loop diagrams is likely to provide new insights into the emergent properties of complex systems and analysing central drivers has the potential to identify leverage points. The results found the structure of the obesity causal loop diagram to resemble commonly observed empirical networks known for efficient spread of information. Known drivers of obesity were found to be the most central variables along with others unique to obesity prevention in the community. While causal loop diagrams are often specific to single communities, the analytic methods provide means to contrast and compare multiple causal loop diagrams for complex problems.

Interaction between poor glycemic control and 9p21 locus on risk of coronary artery disease in type 2 diabetes.

CONTEXT: A common allele on chromosome 9p21 has been repeatedly associated with increased risk of coronary artery disease (CAD) in the general population. However, the magnitude of this effect in the population with diabetes has not been well characterized. OBJECTIVE: To examine the association of the 9p21 variant with CAD in individuals with type 2 diabetes and evaluate its interaction with poor glycemic control. DESIGN, SETTING, AND PARTICIPANTS: (1) Case-control study of 734 type 2 diabetes patients (322 with angiographically diagnosed CAD and 412 with no evidence of CAD) who were recruited between 2001 and 2006 at the Joslin Clinic, Beth Israel Deaconess Medical Center; and (2) independent cohort study of 475 type 2 diabetes patients from the Joslin Clinic whose survival status was monitored from their recruitment between 1993 and 1996 until December 31, 2004. Participants for both studies were genotyped for a representative single-nucleotide polymorphism at 9p21 (rs2383206) and characterized for their long-term glycemic control by averaging multiple hemoglobin A(1c) (HbA(1c)) measurements taken in the years before study entry. MAIN OUTCOME MEASURES: For the case-control study, association between single-nucleotide polymorphism rs2383206 and CAD defined as angiographically documented stenosis greater than 50% in a major coronary artery or a main branch thereof was assessed and for the cohort study, cumulative 10-year mortality was documented. RESULTS: Individuals who were homozygous for the risk allele were significantly more frequent among case than control participants (42.3% vs 28.9P = .0002). This association was unaffected by adjustment for cardiovascular risk factors, but the effect of the risk genotype was significantly magnified (adjusted P for interaction = .048) in the presence of poor glycemic control (worst tertile of the distribution of HbA(1c) at examination). Relative to the CAD risk for patients with neither a 9p21 risk allele nor poor glycemic control, the CAD odds for participants having 2 risk alleles but not poor glycemic control were increased 2-fold (odds ratio [OR], 1.99; 95% confidence interval [CI], 1.17-3.41), whereas the odds for study participants with the same genotype and with poor glycemic control were increased 4-fold (OR, 4.27; 95% CI, 2.26-8.01). The interaction was stronger (adjusted P = .005) when a measure of long-term glycemic control (7-year average rather than most recent HbA(1c)) was used with ORs of 7.83 (95% CI, 3.49-17.6) for participants having 2 risk alleles and a history of poor glycemia and 1.54 (95% CI, 0.72-3.30) for participants with the same genotype but without this exposure. A similar interaction between 9p21 variant and poor glycemic control was observed with respect to cumulative 10-year mortality in the cohort study (43.6% in patients with 2 risk alleles and poor glycemic control, 23.1% in individuals with only the 2 risk alleles, 30.0% in individuals with only poor glycemic control, and 31.6% in individuals with neither factor, P for interaction, = .036). CONCLUSION: In this study population, the CAD risk associated with the 9p21 variant was increased in the presence of poor glycemic control in type 2 diabetes.

Tag polymorphisms at the A20 (TNFAIP3) locus are associated with lower gene expression and increased risk of coronary artery disease in type 2 diabetes.

A20 or tumor necrosis factor (TNF)-induced protein 3 (TNFAIP3) is a negative regulator of nuclear factor-kappaB (NF-kappaB). We have investigated whether polymorphisms in this gene are associated with increased atherosclerosis in diabetic patients. Five tag single nucleotide polymorphisms (SNPs) were typed in 479 type 2 diabetic patients from Boston, including 239 coronary artery disease (CAD)-positive case subjects and 240 CAD-negative control subjects. Two tag SNPs (rs5029930 and rs610604) were independently associated with CAD; adjusted odds ratios (ORs) for minor allele carriers were 2.3 (95% CI 1.4-3.8, P = 0.001) and 2.0 (1.3-2.9, P = 0.0008), respectively. The association with rs610604 was dependent on glycemic control, with ORs of 3.9 among subjects with A1C < or =7.0% and 1.2 for those with A1C >7.0% (P for interaction = 0.015). A similar interaction pattern was found among 231 CAD-positive and 332 CAD-negative type 2 diabetic patients from Italy (OR 2.2, P = 0.05 vs. OR 0.9, P = 0.63 in the low vs. high A1C strata, P for interaction = 0.05). Quantitative RT-PCR in blood mononuclear cells from 83 nondiabetic subjects showed that rs610604 and rs5029930 minor allele homozygotes have 30-45% lower levels of A20 mRNA than major allele homozygotes, and heterozygotes have intermediate levels (P = 0.04 and 0.028, respectively). These findings point to variability in the A20/TNFAIP3 gene as a modulator of CAD risk in type 2 diabetes. This effect is mediated by allelic differences in A20 expression.