Use of Multiple Metabolic and Genetic Markers to Improve the Prediction of Type 2 Diabetes: the EPIC-Potsdam Study

OBJECTIVE — We investigated whether metabolic biomarkers and single nucleotide poly-morphisms (SNPs) improve diabetes prediction beyond age, anthropometry, and lifestyle risk factors. RESEARCH DESIGN AND METHODS — A case-cohort study within a prospective study was designed. We randomly selected a subcohort (n 2,500) from 26,444 participants, of whom 1,962 were diabetes free at baseline. Of the 801 incident type 2 diabetes cases identified in the cohort during 7 years of follow-up, 579 remained for analyses after exclusions. Prediction models were compared by receiver operatoring characteristic (ROC) curve and integrated dis-crimination improvement. RESULTS — Case-control discrimination by the lifestyle characteristics (ROC-AUC: 0.8465) im-proved with plasma glucose (ROC-AUC: 0.8672, P 0.001) and A1C (ROC-AUC: 0.8859, P 0.001). ROC-AUC further improved with HDL cholesterol, triglycerides, -glutamyltransferase, and alanine aminotransferase (0.9000, P 0.002). Twenty SNPs did not improve discrimination beyond these characteristics (P 0.69). CONCLUSIONS — Metabolic markers, but not genotyping for 20 diabetogenic SNPs, im-prove discrimination of incident type 2 diabetes beyond lifestyle risk factors. Diabetes Care 32:2116–2119, 2009 A ccurate identification of individualswho are at increased risk for type 2diabetes is a requirement for a tar-geted prevention. We therefore tested whether metabolic and genetic markers add substantial prognostic information to age, anthropometry, and lifestyle characteristics

Effectiveness of Transmitted Drug Resistance Testing Before Initiation of Antiretroviral Therapy in HIV-Positive Individuals

BACKGROUND For people living with HIV, major guidelines in high-income countries recommend testing for transmitted drug resistance (TDR) to guide the choice of first-line antiretroviral therapy (ART). However, individuals who fail a first-line regimen can now be switched to one of several effective regimens. Therefore, the virological and clinical benefit of TDR testing needs to be evaluated. METHODS We included individuals from the HIV-CAUSAL Collaboration who enrolled <6 months of HIV diagnosis between 2006 and 2015, were ART-naive, and had measured CD4 count and HIV-RNA. Follow-up started at the date when all inclusion criteria were first met (baseline). We compared 2 strategies: (1) TDR testing within 3 months of baseline versus (2) no TDR testing. We used inverse probability weighting to estimate the 5-year proportion and hazard ratios (HRs) of virological suppression (confirmed HIV-RNA <50 copies/mL), and of AIDS or death under both strategies. RESULTS Of 25,672 eligible individuals (82% males, 52% diagnosed in 2010 or later), 17,189 (67%) were tested for TDR within 3 months of baseline. Of these, 6% had intermediate- or high-level TDR to any antiretroviral drug. The estimated 5-year proportion virologically suppressed was 77% under TDR testing and 74% under no TDR testing; HR 1.06 (95% confidence interval: 1.03 to 1.19). The estimated 5-year risk of AIDS or death was 6% under both strategies; HR 1.03 (95% confidence interval: 0.95 to 1.12). CONCLUSIONS TDR prevalence was low. Although TDR testing improved virological response, we found no evidence that it reduced the incidence of AIDS or death in first 5 years after diagnosis

Primary mucinous adenocarcinoma in a defunctionalized urinary bladder: a case report

<p>Abstract</p> <p>Introduction</p> <p>Malignancies are rare in defunctionalized bladders and are thought to arise from metaplasia secondary to chronic inflammation. Transitional cell and squamous cell carcinomas are the most common but there are three reported cases of mucinous adenocarcinoma.</p> <p>Case presentation</p> <p>We report a 57-year-old Caucasian man presenting with penile discharge for 30 years following ileal conduit surgery for neurogenic bladder, and who was found to have primary mucinous adenocarcinoma of his defunctionalized bladder.</p> <p>Conclusion</p> <p>Although urinary diversion without cystectomy is less common in current urologic practice, there are many patients with longstanding defunctionalized bladders. While there are no established surveillance protocols, defunctionalized bladder patients with urethral discharge should be evaluated.</p

Heterogeneous clinical spectrum of DNAJC12-deficient hyperphenylalaninemia:From attention deficit to severe dystonia and intellectual disability

BACKGROUND: Autosomal recessive mutations in DNAJC12, encoding a cochaperone of HSP70 with hitherto unknown function, were recently described to lead to hyperphenylalaninemia, central monoamine neurotransmitter (dopamine and serotonin) deficiency, dystonia and intellectual disability in six subjects affected by homozygous variants. OBJECTIVE: Patients exhibiting hyperphenylalaninemia in whom deficiencies in hepatic phenylalanine hydroxylase and tetrahydrobiopterin cofactor metabolism had been excluded were subsequently analysed for DNAJC12 variants. METHODS: To analyse DNAJC12, genomic DNA from peripheral blood (Sanger sequencing), as well as quantitative messenger RNA (Real Time Quantitative Polymerase Chain Reaction (RT-qPCR)) and protein expression (Western blot) from primary skin fibroblasts were performed. RESULTS: We describe five additional patients from three unrelated families with homozygosity/compound heterozygosity in DNAJC12 with three novel variants: c.85delC/p.Gln29Lysfs*38, c.596G>T/p.*199Leuext*42 and c.214C>T/p.(Arg72*). In contrast to previously reported DNAJC12-deficient patients, all five cases showed a very mild neurological phenotype. In two subjects, cerebrospinal fluid and primary skin fibroblasts were analysed showing similarly low 5-hydroxyindolacetic acid and homovanillic acid concentrations but more reduced expressions of mRNA and DNAJC12 compared with previously described patients. All patients responded to tetrahydrobiopterin challenge by lowering blood phenylalanine levels. CONCLUSIONS: DNAJC12 deficiency appears to result in a more heterogeneous neurological phenotype than originally described. While early identification and institution of treatment with tetrahydrobiopterin and neurotransmitter precursors is crucial to ensure optimal neurological outcome in DNAJC12-deficient patients with a severe phenotype, optimal treatment for patients with a milder phenotype remains to be defined

Modularization of biochemical networks based on classification of Petri net t-invariants

<p>Abstract</p> <p>Background</p> <p>Structural analysis of biochemical networks is a growing field in bioinformatics and systems biology. The availability of an increasing amount of biological data from molecular biological networks promises a deeper understanding but confronts researchers with the problem of combinatorial explosion. The amount of qualitative network data is growing much faster than the amount of quantitative data, such as enzyme kinetics. In many cases it is even impossible to measure quantitative data because of limitations of experimental methods, or for ethical reasons. Thus, a huge amount of qualitative data, such as interaction data, is available, but it was not sufficiently used for modeling purposes, until now. New approaches have been developed, but the complexity of data often limits the application of many of the methods. Biochemical Petri nets make it possible to explore static and dynamic qualitative system properties. One Petri net approach is model validation based on the computation of the system's invariant properties, focusing on t-invariants. T-invariants correspond to subnetworks, which describe the basic system behavior.</p> <p>With increasing system complexity, the basic behavior can only be expressed by a huge number of t-invariants. According to our validation criteria for biochemical Petri nets, the necessary verification of the biological meaning, by interpreting each subnetwork (t-invariant) manually, is not possible anymore. Thus, an automated, biologically meaningful classification would be helpful in analyzing t-invariants, and supporting the understanding of the basic behavior of the considered biological system.</p> <p>Methods</p> <p>Here, we introduce a new approach to automatically classify t-invariants to cope with network complexity. We apply clustering techniques such as UPGMA, Complete Linkage, Single Linkage, and Neighbor Joining in combination with different distance measures to get biologically meaningful clusters (t-clusters), which can be interpreted as modules. To find the optimal number of t-clusters to consider for interpretation, the cluster validity measure, Silhouette Width, is applied.</p> <p>Results</p> <p>We considered two different case studies as examples: a small signal transduction pathway (pheromone response pathway in <it>Saccharomyces cerevisiae</it>) and a medium-sized gene regulatory network (gene regulation of Duchenne muscular dystrophy). We automatically classified the t-invariants into functionally distinct t-clusters, which could be interpreted biologically as functional modules in the network. We found differences in the suitability of the various distance measures as well as the clustering methods. In terms of a biologically meaningful classification of t-invariants, the best results are obtained using the Tanimoto distance measure. Considering clustering methods, the obtained results suggest that UPGMA and Complete Linkage are suitable for clustering t-invariants with respect to the biological interpretability.</p> <p>Conclusion</p> <p>We propose a new approach for the biological classification of Petri net t-invariants based on cluster analysis. Due to the biologically meaningful data reduction and structuring of network processes, large sets of t-invariants can be evaluated, allowing for model validation of qualitative biochemical Petri nets. This approach can also be applied to elementary mode analysis.</p

Chromosomal-level assembly of the Asian Seabass genome using long sequence reads and multi-layered scaffolding

We report here the ~670 Mb genome assembly of the Asian seabass (Lates calcarifer), a tropical marine teleost. We used long-read sequencing augmented by transcriptomics, optical and genetic mapping along with shared synteny from closely related fish species to derive a chromosome-level assembly with a contig N50 size over 1 Mb and scaffold N50 size over 25 Mb that span ~90% of the genome. The population structure of L. calcarifer species complex was analyzed by re-sequencing 61 individuals representing various regions across the species' native range. SNP analyses identified high levels of genetic diversity and confirmed earlier indications of a population stratification comprising three clades with signs of admixture apparent in the South-East Asian population. The quality of the Asian seabass genome assembly far exceeds that of any other fish species, and will serve as a new standard for fish genomics

Trends in Cancer Incidence in Different Antiretroviral Treatment-Eras amongst People with HIV

Despite cancer being a leading comorbidity amongst individuals with HIV, there are limited data assessing cancer trends across different antiretroviral therapy (ART)-eras. We calculated age-standardised cancer incidence rates (IRs) from 2006-2021 in two international cohort collaborations (D:A:D and RESPOND). Poisson regression was used to assess temporal trends, adjusted for potential confounders. Amongst 64,937 individuals (31% ART-naïve at baseline) and 490,376 total person-years of follow-up (PYFU), there were 3763 incident cancers (IR 7.7/1000 PYFU [95% CI 7.4, 7.9]): 950 AIDS-defining cancers (ADCs), 2813 non-ADCs, 1677 infection-related cancers, 1372 smoking-related cancers, and 719 BMI-related cancers (groups were not mutually exclusive). Age-standardised IRs for overall cancer remained fairly constant over time (8.22/1000 PYFU [7.52, 8.97] in 2006-2007, 7.54 [6.59, 8.59] in 2020-2021). The incidence of ADCs (3.23 [2.79, 3.72], 0.99 [0.67, 1.42]) and infection-related cancers (4.83 [4.2, 5.41], 2.43 [1.90, 3.05]) decreased over time, whilst the incidence of non-ADCs (4.99 [4.44, 5.58], 6.55 [5.67, 7.53]), smoking-related cancers (2.38 [2.01, 2.79], 3.25 [2.63-3.96]), and BMI-related cancers (1.07 [0.83, 1.37], 1.88 [1.42, 2.44]) increased. Trends were similar after adjusting for demographics, comorbidities, HIV-related factors, and ART use. These results highlight the need for better prevention strategies to reduce the incidence of NADCs, smoking-, and BMI-related cancers

Frequent Dilatation of the Descending Aorta in Children With Hypoplastic Left Heart Syndrome Relates to Decreased Aortic Arch Elasticity

Background: Patients with hypoplastic left heart syndrome after a Norwood operation show dilatation and reduced distensibility of the reconstructed proximal aorta. Cardiac magnetic resonance imaging (CMR) and angiographic examinations indicate that the native descending aorta (DAo) is also dilated, but this has not been studied in detail. Methods and Results: Seventy‐nine children with hypoplastic left heart syndrome in Fontan circulation (aged 6.3±3.2 years) and 18 control participants (aged 6.8±2.4 years) underwent 3.0‐tesla CMR. Gradient‐echo cine and phase‐contrast imaging was applied to measure cross‐sectional areas (CSAs), distensibility, pulse wave velocity, and the incremental elastic modulus of the thoracic aorta. CSA of the DAo in patients was also compared with published percentiles for aortic CSA. Patients had significantly larger CSA of the DAo at the level of pulmonary artery bifurcation (229.1±97.2 versus 175.7±24.3 mm/m2, P=0.04) and the diaphragm (196.2±66.0 versus 142.6±16.7 mm/m2, P95th percentile level for control participants, and the incremental elastic modulus of the aortic arch and the DAo was higher than in patients with normal CSAs (arch: 90.1±64.3 versus 45.6±38.9 m/s; DAo: 86.3±53.7 versus 47.1±47.6 m/s; P<0.01). Incremental elastic modulus of the aortic arch and the DAo correlated with the CSA of the DAo (arch: r=0.5; DAo: r=0.49; P<0.01). Conclusions: Children with hypoplastic left heart syndrome frequently show dilatation of their DAo associated with increased stiffness of the aortic arch. Higher aortic impedance increases the afterload of the systemic circulation and likely contributes to the burden of the systemic right ventricle