A review of genetic variant databases and machine learning tools for predicting the pathogenicity of breast cancer.

Studies continue to uncover contributing risk factors for breast cancer (BC) development including genetic variants. Advances in machine learning and big data generated from genetic sequencing can now be used for predicting BC pathogenicity. However, it is unclear which tool developed for pathogenicity prediction is most suited for predicting the impact and pathogenicity of variant effects. A significant challenge is to determine the most suitable data source for each tool since different tools can yield different prediction results with different data inputs. To this end, this work reviews genetic variant databases and tools used specifically for the prediction of BC pathogenicity. We provide a description of existing genetic variants databases and, where appropriate, the diseases for which they have been established. Through example, we illustrate how they can be used for prediction of BC pathogenicity and discuss their associated advantages and disadvantages. We conclude that the tools that are specialized by training on multiple diverse datasets from different databases for the same disease have enhanced accuracy and specificity and are thereby more helpful to the clinicians in predicting and diagnosing BC as early as possible.

A surge in serum mucosal cytokines associated with seroconversion in children at risk for type 1 diabetes.

AIMS/INTRODUCTION: Autoantibodies to pancreatic islet antigens identify young children at high risk of type 1 diabetes. On a background of genetic susceptibility, islet autoimmunity is thought to be driven by environmental factors, of which enteric viruses are prime candidates. We sought evidence for enteric pathology in children genetically at-risk for type 1 diabetes followed from birth who had developed islet autoantibodies ("seroconverted"), by measuring mucosa-associated cytokines in their sera. MATERIALS AND METHODS: Sera were collected 3 monthly from birth from children with a first-degree type 1 diabetes relative, in the Environmental Determinants of Islet Autoimmunity (ENDIA) study. Children who seroconverted were matched for sex, age, and sample availability with seronegative children. Luminex xMap technology was used to measure serum cytokines. RESULTS: Of eight children who seroconverted, for whom serum samples were available at least 6 months before and after seroconversion, the serum concentrations of mucosa-associated cytokines IL-21, IL-22, IL-25, and IL-10, the Th17-related cytokines IL-17F and IL-23, as well as IL-33, IFN-γ, and IL-4, peaked from a low baseline in seven around the time of seroconversion and in one preceding seroconversion. These changes were not detected in eight sex- and age-matched seronegative controls, or in a separate cohort of 11 unmatched seronegative children. CONCLUSIONS: In a cohort of children at risk for type 1 diabetes followed from birth, a transient, systemic increase in mucosa-associated cytokines around the time of seroconversion lends support to the view that mucosal infection, e.g., by an enteric virus, may drive the development of islet autoimmunity.

Protocol for a nested case-control study design for omics investigations in the Environmental Determinants of Islet Autoimmunity cohort.

Background: The Environmental Determinants of Islet Autoimmunity (ENDIA) pregnancy-birth cohort investigates the developmental origins of type 1 diabetes (T1D), with recruitment between 2013 and 2019. ENDIA is the first study in the world with comprehensive data and biospecimen collection during pregnancy, at birth and through childhood from at-risk children who have a first-degree relative with T1D. Environmental exposures are thought to drive the progression to clinical T1D, with pancreatic islet autoimmunity (IA) developing in genetically susceptible individuals. The exposures and key molecular mechanisms driving this progression are unknown. Persistent IA is the primary outcome of ENDIA; defined as a positive antibody for at least one of IAA, GAD, ZnT8 or IA2 on two consecutive occasions and signifies high risk of clinical T1D.Method: A nested case-control (NCC) study design with 54 cases and 161 matched controls aims to investigate associations between persistent IA and longitudinal omics exposures in ENDIA. The NCC study will analyse samples obtained from ENDIA children who have either developed persistent IA or progressed to clinical T1D (cases) and matched control children at risk of developing persistent IA. Control children were matched on sex and age, with all four autoantibodies absent within a defined window of the case's onset date. Cases seroconverted at a median of 1.37 years (IQR 0.95, 2.56). Longitudinal omics data generated from approximately 16,000 samples of different biospecimen types, will enable evaluation of changes from pregnancy through childhood.Conclusions: This paper describes the ENDIA NCC study, omics platform design considerations and planned univariate and multivariate analyses for its longitudinal data. Methodologies for multivariate omics analysis with longitudinal data are discovery-focused and data driven. There is currently no single multivariate method tailored specifically for the longitudinal omics data that the ENDIA NCC study will generate and therefore omics analysis results will require either cross validation or independent validation.KEY MESSAGESThe ENDIA nested case-control study will utilize longitudinal omics data on approximately 16,000 samples from 190 unique children at risk of type 1 diabetes (T1D), including 54 who have developed islet autoimmunity (IA), followed during pregnancy, at birth and during early childhood, enabling the developmental origins of T1D to be explored.

A GDPR-Compliant Dynamic Consent Mobile Application for the Australasian Type-1 Diabetes Data Network.

Australia has a high prevalence of diabetes, with approximately 1.2 million Australians diagnosed with the disease. In 2012, the Australasian Diabetes Data Network (ADDN) was established with funding from the Juvenile Diabetes Research Foundation (JDRF). ADDN is a national diabetes registry which captures longitudinal information about patients with type-1 diabetes (T1D). Currently, the ADDN data are directly contributed from 42 paediatric and 17 adult diabetes centres across Australia and New Zealand, i.e., where the data are pre-existing in hospital systems and not manually entered into ADDN. The historical data in ADDN have been de-identified, and patients are initially afforded the opportunity to opt-out of being involved in the registry; however, moving forward, there is an increased demand from the clinical research community to utilise fully identifying data. This raises additional demands on the registry in terms of security, privacy, and the nature of patient consent. General Data Protection Regulation (GDPR) is an increasingly important mechanism allowing individuals to have the right to know about their health data and what those data are being used for. This paper presents a mobile application being designed to support the ADDN data collection and usage processes and aligning them with GDPR. The app utilises Dynamic Consent-an informed specific consent model, which allows participants to view and modify their research-driven consent decisions through an interactive interface. It focuses specifically on supporting dynamic opt-in consent to both the registry and to associated sub-projects requesting access to and use of the patient data for research purposes.

Predicting reliability through structured expert elicitation with the repliCATS (Collaborative Assessments for Trustworthy Science) process.

As replications of individual studies are resource intensive, techniques for predicting the replicability are required. We introduce the repliCATS (Collaborative Assessments for Trustworthy Science) process, a new method for eliciting expert predictions about the replicability of research. This process is a structured expert elicitation approach based on a modified Delphi technique applied to the evaluation of research claims in social and behavioural sciences. The utility of processes to predict replicability is their capacity to test scientific claims without the costs of full replication. Experimental data supports the validity of this process, with a validation study producing a classification accuracy of 84% and an Area Under the Curve of 0.94, meeting or exceeding the accuracy of other techniques used to predict replicability. The repliCATS process provides other benefits. It is highly scalable, able to be deployed for both rapid assessment of small numbers of claims, and assessment of high volumes of claims over an extended period through an online elicitation platform, having been used to assess 3000 research claims over an 18 month period. It is available to be implemented in a range of ways and we describe one such implementation. An important advantage of the repliCATS process is that it collects qualitative data that has the potential to provide insight in understanding the limits of generalizability of scientific claims. The primary limitation of the repliCATS process is its reliance on human-derived predictions with consequent costs in terms of participant fatigue although careful design can minimise these costs. The repliCATS process has potential applications in alternative peer review and in the allocation of effort for replication studies.

Evaluating untimed and timed abridged versions of Raven's Advanced Progressive Matrices.

INTRODUCTION: Raven's Advanced Progressive Matrices (APM) are frequently utilized in clinical and experimental settings to index intellectual capacity. As the APM is a relatively long assessment, abridged versions of the test have been proposed. The psychometric properties of an untimed 12-item APM have received some consideration in the literature, but validity explorations have been limited. Moreover, both reliability and validity of a timed 12-item APM have not previously been examined. METHOD: We considered the psychometric properties of untimed (Study 1; N = 608; Mage = 27.89, SD = 11.68) and timed (Study 2; N = 479; Mage = 20.93, SD = 3.12) versions of a brief online 12-item form of the APM. RESULTS: Confirmatory factor analyses established both versions of the tests are unidimensional. Item response theory analyses revealed that, in each case, the 12 items are characterized by distinct differences in difficulty, discrimination, and guessing. Differential item functioning showed few male/female or native English/non-native English performance differences. Test-retest reliability was .65 (Study 1) to .69 (Study 2). Both tests had medium-to-large correlations with the Wechsler Abbreviated Scale of Intelligence (2nd ed.) Perceptual Reasoning Index (r = .50, Study 1; r = .56, Study 2) and Full-Scale IQ (r = .34, Study 1; r = .41, Study 2). CONCLUSION: In sum, results suggest both untimed and timed online versions of the brief APM are psychometrically sound. As test duration was found to be highly variable for the untimed version, the timed form might be a more suitable choice when it is likely to form part of a longer battery of tests. Nonetheless, classical test and item response theory analyses, plus validity considerations, suggest the untimed version might be the superior abridged form.

Mental Health During Late Pregnancy and Postpartum in Mothers With and Without Type 1 Diabetes: The ENDIA Study.

OBJECTIVE: Pregnancy and type 1 diabetes are each associated with increased anxiety and depression, but the combined impact on well-being is unresolved. We compared the mental health of women with and without type 1 diabetes during pregnancy and postpartum and examined the relationship between mental health and glycemic control. RESEARCH DESIGN AND METHODS: Participants were women enrolled from 2016 to 2020 in the Environmental Determinants of Islet Autoimmunity (ENDIA) study, a pregnancy to birth prospective cohort following children with a first-degree relative with type 1 diabetes. Edinburgh Postnatal Depression Scale (EPDS) and Perceived Stress Scale (PSS) were completed during the third trimester (T3) (median [interquartile range] 34 [32, 36] weeks) and postpartum (14 [13, 16] weeks) by 737 women (800 pregnancies) with (n = 518) and without (n = 282) type 1 diabetes. RESULTS: EPDS and PSS scores did not differ between women with and without type 1 diabetes during T3 and postpartum. EPDS scores were marginally higher in T3: predicted mean (95% CI) 5.7 (5.4, 6.1) than postpartum: 5.3 (5.0, 5.6), independent of type 1 diabetes status (P = 0.01). HbA1c levels in type 1 diabetes were 6.3% [5.8, 6.9%] in T3 and did not correlate with EPDS or PSS scores. Reported use of psychotropic medications was similar in women with (n = 44 of 518 [8%]) and without type 1 diabetes (n = 17 of 282 [6%]), as was their amount of physical activity. CONCLUSIONS: Overall, mental health in late pregnancy and postpartum did not differ between women with and without type 1 diabetes, and mental health scores were not correlated with glycemic control.

Women with type 1 diabetes exhibit a progressive increase in gut Saccharomyces cerevisiae in pregnancy associated with evidence of gut inflammation.

AIMS: Studies of the gut microbiome have focused on its bacterial composition. We aimed to characterize the gut fungal microbiome (mycobiome) across pregnancy in women with and without type 1 diabetes. METHODS: Faecal samples (n = 162) were collected from 70 pregnant women (45 with and 25 without type 1 diabetes) across all trimesters. Fungi were analysed by internal transcribed spacer 1 amplicon sequencing. Markers of intestinal inflammation (faecal calprotectin) and intestinal epithelial integrity (serum intestinal fatty acid binding protein; I-FABP), and serum antibodies to Saccharomyces cerevisiae (ASCA) were measured. RESULTS: Women with type 1 diabetes had decreased fungal alpha diversity by the third trimester, associated with an increased abundance of Saccharomyces cerevisiae that was inversely related to the abundance of the anti-inflammatory butyrate-producing bacterium Faecalibacterium prausnitzii. Women with type 1 diabetes had higher concentrations of calprotectin, I-FABP and ASCA. CONCLUSIONS: Women with type 1 diabetes exhibit a shift in the gut mycobiome across pregnancy associated with evidence of gut inflammation and impaired intestinal barrier function. The relevance of these findings to the higher rate of pregnancy complications in type 1 diabetes warrants further study.

Addressing methodological issues in a study of impulsivity and vulnerability for transition to alcohol use disorder.

BACKGROUND: Heightened behavioral impulsivity has been advocated as a preexisting risk factor for the development of alcohol use disorder (AUD). Nonetheless, studies investigating impulsivity in adolescent/young adult at-risk drinkers-who are at increased risk of developing AUD-report mixed findings. This may be due to methodological limitations related to definitions of at-risk drinking, the retrospective assessment of alcohol intake, and/or the relatively modest sample size of some studies. METHODS: Healthy individuals (N = 814, Mage  = 22.50) completed online surveys and a measure of choice impulsivity. Of these, a number of participants also undertook an online measure of response inhibition (n = 627, Mage  = 22.66), and a further subgroup submitted real-time alcohol consumption information for a period of 21 days using an app (n = 543, Mage  = 22.96). Differences in behavioral impulsivity were assessed as a function of various at-risk alcohol intake categories. Hierarchical multiple regression was employed to determine whether impulsivity predicted alcohol use in the form of a continuous index comprising variables related to intake and consequences of use. RESULTS: Significantly greater impulsivity was not evident in heavy, standard binge, high binge, harmful, or hazardous alcohol drinkers as compared to controls, regardless of the criteria employed to categorize these at-risk drinkers. Neither choice impulsivity nor reduced response inhibition significantly predicted the alcohol use index. CONCLUSIONS: While results could be attributed to the online nature of this research, it is possible that more sensitive measures of behavioral impulsivity are required when assessing nondependent drinkers.

Universal Subsidized Continuous Glucose Monitoring Funding for Young People With Type 1 Diabetes: Uptake and Outcomes Over 2 Years, a Population-Based Study.

OBJECTIVE: Continuous glucose monitoring (CGM) is increasingly used in type 1 diabetes management; however, funding models vary. This study determined the uptake rate and glycemic outcomes following a change in national health policy to introduce universal subsidized CGM funding for people with type 1 diabetes aged <21 years. RESEARCH DESIGN AND METHODS: Longitudinal data from 12 months before the subsidy until 24 months after were analyzed. Measures and outcomes included age, diabetes duration, HbA1c, episodes of diabetic ketoacidosis and severe hypoglycemia, insulin regimen, CGM uptake, and percentage CGM use. Two data sources were used: the Australasian Diabetes Database Network (ADDN) registry (a prospective diabetes database) and the National Diabetes Service Scheme (NDSS) registry that includes almost all individuals with type 1 diabetes nationally. RESULTS: CGM uptake increased from 5% presubsidy to 79% after 2 years. After CGM introduction, the odds ratio (OR) of achieving the HbA1c target of <7.0% improved at 12 months (OR 2.5, P < 0.001) and was maintained at 24 months (OR 2.3, P < 0.001). The OR for suboptimal glycemic control (HbA1c ≥9.0%) decreased to 0.34 (P < 0.001) at 24 months. Of CGM users, 65% used CGM >75% of time, and had a lower HbA1c at 24 months compared with those with usage <25% (7.8 ± 1.3% vs. 8.6 ± 1.8%, respectively, P < 0.001). Diabetic ketoacidosis was also reduced in this group (incidence rate ratio 0.49, 95% CI 0.33-0.74, P < 0.001). CONCLUSIONS: Following the national subsidy, CGM use was high and associated with sustained improvement in glycemic control. This information will inform economic analyses and future policy and serve as a model of evaluation diabetes technologies.

Diabetic Ketoacidosis at Onset of Type 1 Diabetes and Long-term HbA1c in 7,961 Children and Young Adults in the Australasian Diabetes Data Network.

OBJECTIVE: The relationship between diabetic ketoacidosis (DKA) at diagnosis of type 1 diabetes and long-term glycemic control varies between studies. We aimed, firstly, to characterize the association of DKA and its severity with long-term HbA1c in a large contemporary cohort, and secondly, to identify other independent determinants of long-term HbA1c. RESEARCH DESIGN AND METHODS: Participants were 7,961 children and young adults diagnosed with type 1 diabetes by age 30 years from 2000 to 2019 and followed prospectively in the Australasian Diabetes Data Network (ADDN) until 31 December 2020. Linear mixed-effect models related variables to HbA1c. RESULTS: DKA at diagnosis was present in 2,647 participants (33.2%). Over a median 5.6 (interquartile range 3.2, 9.4) years of follow-up, participants with severe, but not moderate or mild, DKA at diagnosis had a higher mean HbA1c (+0.23%, 95% CI 0.11,0.28; [+2.5 mmol/mol, 95% CI 1.4,3.6]; P < 0.001) compared with those without DKA. Use of continuous subcutaneous insulin infusion (CSII) was independently associated with a lower HbA1c (-0.28%, 95% CI -0.31, -0.25; [-3.1 mmol/mol, 95% CI -3.4, -2.8]; P < 0.001) than multiple daily injections, and CSII use interacted with severe DKA to lower predicted HbA1c. Indigenous status was associated with higher HbA1c (+1.37%, 95% CI 1.15, 1.59; [+15.0 mmol/mol, 95% CI 12.6, 17.4]; P < 0.001), as was residing in postcodes of lower socioeconomic status (most vs. least disadvantaged quintile +0.43%, 95% CI 0.34, 0.52; [+4.7 mmol/mol, 95% CI 3.4, 5.6]; P < 0.001). CONCLUSIONS: Severe, but not mild or moderate, DKA at diagnosis was associated with a marginally higher HbA1c over time, an effect that was modified by use of CSII. Indigenous status and lower socioeconomic status were independently associated with higher long-term HbA1c.

An Online, Person-Centered, Risk Factor Management Program to Prevent Cognitive Decline: Protocol for A Prospective Behavior-Modification Blinded Endpoint Randomized Controlled Trial.

BACKGROUND: Several modifiable risk factors for dementia have been identified, although the extent to which their modification leads to improved cognitive outcomes remains unclear. OBJECTIVE: The primary aim is to test the hypothesis that a behavior modification intervention program targeting personalized risk factors prevents cognitive decline in community-dwelling, middle-aged adults with a family history of dementia. METHODS: This is a prospective, risk factor management, blinded endpoint, randomized, controlled trial, where 1510 cognitively normal, community-dwelling adults aged 40-70 years old will be recruited. Participants will be screened for risk factors related to vascular health (including physical inactivity), mental health, sleep, and cognitive/social engagement. The intervention is an online person-centered risk factor management program: BetterBrains. Participants randomized to intervention will receive telehealth-based person-centered goal setting, motivational interviewing, and follow-up support, health care provider communication and community linkage for management of known modifiable risk factors of dementia. Psychoeducational health information will be provided to both control and intervention groups. RESULTS: The primary outcome is favorable cognitive performance at 24-months post-baseline, defined as the absence of decline on one or more of the following cognitive tests: (a) Cogstate Detection, (b) Cogstate One Card Learning, (c) Cogstate One Back, and (d) Cognitive Function Instrument total score. CONCLUSION: We will test the hypothesis that the BetterBrains intervention program can prevent cognitive decline. By leveraging existing community services and using a risk factor management pathway that tailors the intervention to each participant, we maximize likelihood for engagement, long-term adherence, and for preserving cognitive function in at-risk individuals.

CogTale: an online platform for the evaluation, synthesis, and dissemination of evidence from cognitive interventions studies.

Systematic reviews and meta-analyses are critical in health-related decision-making, and are considered the gold standard in research synthesis methods. However, with new trials being regularly published and with the development of increasingly rigorous standards of data synthesis, systematic reviews often require much expertise and long periods of time to be completed. Automation of some of the steps of evidence synthesis productions is a promising improvement in the field, capable of reducing the time and costs associated with the process.This article describes the development and main characteristics of a novel online repository of cognitive intervention studies entitled Cognitive Treatments Article Library and Evaluation (CogTale). The platform is currently in a Beta Release phase, as it is still under development. However, it already contains over 70 studies, and the CogTale team is continuously coding and uploading new studies into the repository. Key features include advanced search options, the capability to generate meta-analyses, and an up-to-date display of relevant published studies.

Type 1 diabetes in pregnancy is associated with distinct changes in the composition and function of the gut microbiome.

BACKGROUND: The gut microbiome changes in response to a range of environmental conditions, life events and disease states. Pregnancy is a natural life event that involves major physiological adaptation yet studies of the microbiome in pregnancy are limited and their findings inconsistent. Pregnancy with type 1 diabetes (T1D) is associated with increased maternal and fetal risks but the gut microbiome in this context has not been characterized. By whole metagenome sequencing (WMS), we defined the taxonomic composition and function of the gut bacterial microbiome across 70 pregnancies, 36 in women with T1D. RESULTS: Women with and without T1D exhibited compositional and functional changes in the gut microbiome across pregnancy. Profiles in women with T1D were distinct, with an increase in bacteria that produce lipopolysaccharides and a decrease in those that produce short-chain fatty acids, especially in the third trimester. In addition, women with T1D had elevated concentrations of fecal calprotectin, a marker of intestinal inflammation, and serum intestinal fatty acid-binding protein (I-FABP), a marker of intestinal epithelial damage. CONCLUSIONS: Women with T1D exhibit a shift towards a more pro-inflammatory gut microbiome during pregnancy, associated with evidence of intestinal inflammation. These changes could contribute to the increased risk of pregnancy complications in women with T1D and are potentially modifiable by dietary means. Video abstract.

Determinants of Cardiovascular Risk in 7000 Youth With Type 1 Diabetes in the Australasian Diabetes Data Network.

CONTEXT: Cardiovascular disease occurs prematurely in type 1 diabetes. The additional risk of overweight is not well characterized. OBJECTIVE: The primary aim was to measure the impact of body mass index (BMI) in youth with type 1 diabetes on cardiovascular risk factors. The secondary aim was to identify other determinants of cardiovascular risk. DESIGN: Observational longitudinal study of 7061 youth with type 1 diabetes followed for median 7.3 (interquartile range [IQR] 4-11) years over 41 (IQR 29-56) visits until March 2019. SETTING: 15 tertiary care diabetes centers in the Australasian Diabetes Data Network.Participants were aged 2 to 25 years at baseline, with at least 2 measurements of BMI and blood pressure. MAIN OUTCOME MEASURE: Standardized systolic and diastolic blood pressure scores and non-high-density lipoprotein (HDL) cholesterol were co-primary outcomes. Urinary albumin/creatinine ratio was the secondary outcome. RESULTS: BMI z-score related independently to standardized blood pressure z- scores and non-HDL cholesterol. An increase in 1 BMI z-score related to an average increase in systolic/diastolic blood pressure of 3.8/1.4 mmHg and an increase in non-HDL cholesterol (coefficient + 0.16 mmol/L, 95% confidence interval [CI], 0.13-0.18; P < 0.001) and in low-density lipoprotein (LDL) cholesterol. Females had higher blood pressure z-scores, higher non-HDL and LDL cholesterol, and higher urinary albumin/creatinine than males. Indigenous youth had markedly higher urinary albumin/creatinine (coefficient + 2.15 mg/mmol, 95% CI, 1.27-3.03; P < 0.001) and higher non-HDL cholesterol than non-Indigenous youth. Continuous subcutaneous insulin infusion was associated independently with lower non-HDL cholesterol and lower urinary albumin/creatinine. CONCLUSIONS: BMI had a modest independent effect on cardiovascular risk. Females and Indigenous Australians in particular had a more adverse risk profile.

Glucocorticoid Excess in Patients with Pheochromocytoma Compared with Paraganglioma and Other Forms of Hypertension.

CONTEXT: Catecholamines and adrenocortical steroids are important regulators of blood pressure. Bidirectional relationships between adrenal steroids and catecholamines have been established but whether this is relevant to patients with pheochromocytoma is unclear. OBJECTIVE: This study addresses the hypothesis that patients with pheochromocytoma and paraganglioma (PPGL) have altered steroid production compared with patients with primary hypertension. DESIGN: Multicenter cross-sectional study. SETTING: Twelve European referral centers. PATIENTS: Subjects included 182 patients with pheochromocytoma, 36 with paraganglioma and 270 patients with primary hypertension. Patients with primary aldosteronism (n = 461) and Cushing syndrome (n = 124) were included for additional comparisons. INTERVENTION: In patients with PPGLs, surgical resection of tumors. OUTCOME MEASURES: Differences in mass spectrometry-based profiles of 15 adrenal steroids between groups and after surgical resection of PPGLs. Relationships of steroids to plasma and urinary metanephrines and urinary catecholamines. RESULTS: Patients with pheochromocytoma had higher (P < .05) circulating concentrations of cortisol, 11-deoxycortisol, 11-deoxycorticosterone, and corticosterone than patients with primary hypertension. Concentrations of cortisol, 11-deoxycortisol, and corticosterone were also higher (P < .05) in patients with pheochromocytoma than with paraganglioma. These steroids correlated positively with plasma and urinary metanephrines and catecholamines in patients with pheochromocytoma, but not paraganglioma. After adrenalectomy, there were significant decreases in cortisol, 11-deoxycortisol, corticosterone, 11-deoxycorticosterone, aldosterone, and 18-oxocortisol. CONCLUSIONS: This is the first large study in patients with PPGLs that supports in a clinical setting the concept of adrenal cortical-medullary interactions involving an influence of catecholamines on adrenal steroids. These findings could have implications for the cardiovascular complications of PPGLs and the clinical management of patients with the tumors.

Comparison of Optimization-Modelling Methods for Metabolites Production in Escherichia coli.

The metabolic network is the reconstruction of the metabolic pathway of an organism that is used to represent the interaction between enzymes and metabolites in genome level. Meanwhile, metabolic engineering is a process that modifies the metabolic network of a cell to increase the production of metabolites. However, the metabolic networks are too complex that cause problem in identifying near-optimal knockout genes/reactions for maximizing the metabolite's production. Therefore, through constraint-based modelling, various metaheuristic algorithms have been improvised to optimize the desired phenotypes. In this paper, PSOMOMA was compared with CSMOMA and ABCMOMA for maximizing the production of succinic acid in E. coli. Furthermore, the results obtained from PSOMOMA were validated with results from the wet lab experiment.

Changes in pancreatic exocrine function in young at-risk children followed to islet autoimmunity and type 1 diabetes in the ENDIA study.

BACKGROUNDS: We aimed to monitor pancreatic exocrine function longitudinally in relation to the development of islet autoimmunity (IA) and type 1 diabetes (T1D) in at-risk children with a first-degree relative with T1D, who were followed prospectively in the Environmental Determinants of Islet Autoimmunity (ENDIA) study. METHODS: Fecal elastase-1 (FE-1) concentration was measured longitudinally in 85 ENDIA children from median age 1.0 (IQR 0.7,1.3) year. Twenty-eight of 85 children (progressors) developed persistent islet autoantibodies at median age of 1.5 (IQR 1.1,2.5) years, of whom 11 went on to develop clinical diabetes. The other 57 islet autoantibody-negative children (non-progressors) followed similarly were age and gender-matched with the progressors. An adjusted linear mixed model compared FE-1 concentrations in progressors and non-progressors. RESULTS: Baseline FE-1 did not differ between progressors and non-progressors, or by HLA DR type or proband status. FE-1 decreased over time in progressors in comparison to non-progressors (Wald statistic 5.46, P = .02); in some progressors the fall in FE-1 preceded the onset of IA. CONCLUSIONS: Pancreatic exocrine function decreases in the majority of young at-risk children who progress to IA and T1D.