No evidence for increased self-reported cognitive failure in Type 1 and Type 2 diabetes:A cross-sectional study

Aims: Mild cognitive deficits have been determined in both types of diabetes using neurocognitive tests. Little is known about the degree to which patients complain about their cognitive functioning. This study set out to investigate the magnitude and correlates of self-reported cognitive failure in adult out-patients with Type 1 and Type 2 diabetes. Methods: Subjective cognitive functioning was measured in 187 diabetic patients using the Cognitive Failures Questionnaire (CFQ). Demographic and clinical characteristics were retrieved from the medical records. The Patient Health Questionnaire 9 items (PHQ-9) was self-administered along with the CFQ to correct for the confounding effect of depression. Results: Analyses were based on 55 patients with Type 1 diabetes and 100 patients with Type 2 diabetes. No difference in mean CFQ score was observed between Type 1 and Type 2 diabetic patients or between Type 1 diabetic patients and healthy control subjects. Female patients with Type 2 diabetes reported significantly fewer cognitive complaints compared with female healthy control subjects. None of the demographic variables and diabetes-related complications was associated with subjective cognitive complaints. A strong positive association was found between depression symptomatology and frequency of self-reported cognitive failure. Conclusions: Our study could not confirm elevated subjective cognitive complaints in a group of Type 1 and Type 2 diabetes patients, as might be expected given the observed elevated rates of mild cognitive dysfunction in patients with diabetes. Self-reported cognitive failure appears largely determined by depressive symptomatology. Therefore, affective status should be included in any cognitive assessment procedure

Contribution of citizen science to improve knowledge on marine biodiversity in the Gulf Region

Monitoring marine biodiversity is costly and practical solutions have to be implemented to identify species and their preferred habitats, particularly in this era of rapid global change. Citizen science has proven to be effective and with high potential for monitoring efforts, and has been extensively applied to biodiversity. We have used the citizen science approach to engage the general public and stakeholders to contribute improving the current knowledge of sea snake biodiversity in Qatar and the Gulf Region. Logistic regression analysis using demographic data from interview surveys conducted in Qatar has indicated that the people having seen more sea snakes are older than 30 years and are Qatari citizens and/or fishermen from India. Of the ten species of sea snakes listed in the literature to be present in the Gulf Region, most of them have been reported for Qatar, Bahrain, United Arab Emirates and Saudi Arabia. However, the number of species present is often assumed based on their occurrence within the Arabian Gulf rather than on actual captures and appropriate identification. The creation of marine reference biological scientific collections to properly identify the species and make accurate biodiversity inventories is an urgent priority for the countries in the Gulf region. To this end, contributions by stakeholders and the general public for this study have proven to be very useful. However a larger networking with local and international scientists and stakeholders is still needed to adequately survey the country''s current biodiversity, identify research priorities and eventually provide the scientific input needed to assist biodiversity management related to renewable resource management and marine conservation in the Arabian Gulf Region

Best packing of rods into boxes

AbstractWe determine the maximum number of 1 × 1 x … × 1 × n rods which will fit inside an arbitrary d-dimensional rectangular box, on condition that they be packed parallel to the edges of the box

A COMBINED MEASURE OF COGNITION AND FUNCTION FOR CLINICAL TRIALS: THE INTEGRATED ALZHEIMER’S DISEASE RATING SCALE (IADRS)

It is generally recognized that more sensitive instruments for the earliest stages of Alzheimer’s disease (AD) are needed. The integrated Alzheimer’s Disease Rating Scale (iADRS) combines scores from 2 widely accepted measures, the Alzheimer’s Disease Assessment Scale-Cognitive subscale (ADAS-Cog) and the Alzheimer’s Disease Cooperative Study – instrumental Activities of Daily Living (ADCS-iADL). Disease progression and treatment differences as measured by the iADRS were analyzed using data from solanezumab EXPEDITION, EXPEDITION2, and EXPEDITION-EXT Studies; semagacestat IDENTITY Study; and donepezil ADCS – mild cognitive impairment (ADCS-MCI) Study. Psychometric properties of the iADRS were established through principal component analysis (PCA) and estimation of contributions of subscores and individual item scores to the iADRS total score. The iADRS performed better than most composites and scales in detecting disease progression and comparably or better than individual scales in detecting treatment differences. PCA demonstrated the iADRS can be divided into two principal components primarily representing cognitive items and instrumental ADLs. Dynamic ranges of the subscales were similar across all studies, reflecting approximately equal contributions from both subscales to the iADRS total score. In item analyses, every item contributed to the total score, with varying strength of contributions by item and across data sets. The iADRS demonstrated acceptable psychometric properties and was effective in capturing disease progression from MCI through moderate AD and treatment effects across the early disease spectrum. These findings suggest the iADRS can be used in studies of mixed populations, ensuring sensitivity to treatment effects as subjects progress during studies of putative disease-modifying agents

The arrhythmogenic cardiomyopathy phenotype associated with PKP2 c.1211dup variant

Background: The arrhythmogenic cardiomyopathy (ACM) phenotype, with life-threatening ventricular arrhythmias and heart failure, varies according to genetic aetiology. We aimed to characterise the phenotype associated with the variant c.1211dup (p.Val406Serfs*4) in the plakophilin‑2 gene (PKP2) and compare it with previously reported Dutch PKP2 founder variants. Methods: Clinical data were collected retrospectively from medical records of 106 PKP2 c.1211dup heterozygous carriers. Using data from the Netherlands ACM Registry, c.1211dup was compared with 3 other truncating PKP2 variants (c.235C &gt; T (p.Arg79*), c.397C &gt; T (p.Gln133*) and c.2489+1G &gt; A (p.?)). Results: Of the 106 carriers, 47 (44%) were diagnosed with ACM, at a mean age of 41 years. By the end of follow-up, 29 (27%) had experienced sustained ventricular arrhythmias and 12 (11%) had developed heart failure, with male carriers showing significantly higher risks than females on these endpoints (p &lt; 0.05). Based on available cardiac magnetic resonance imaging and echocardiographic data, 46% of the carriers showed either right ventricular dilatation and/or dysfunction, whereas a substantial minority (37%) had some form of left ventricular involvement. Both geographical distribution of carriers and haplotype analysis suggested PKP2 c.1211dup to be a founder variant originating from the South-Western coast of the Netherlands. Finally, a Cox proportional hazards model suggested significant differences in ventricular arrhythmia–free survival between 4 PKP2 founder variants, including c.1211dup. Conclusions: The PKP2 c.1211dup variant is a Dutch founder variant associated with a typical right-dominant ACM phenotype, but also left ventricular involvement, and a possibly more severe phenotype than other Dutch PKP2 founder variants.</p

NPHP4 Variants Are Associated With Pleiotropic Heart Malformations

Rationale: Congenital heart malformations are a major cause of morbidity and mortality, especially in young children. Failure to establish normal left-right (L-R) asymmetry often results in cardiovascular malformations and other laterality defects of visceral organs. Objective: To identify genetic mutations causing cardiac laterality defects. Methods and Results: We performed a genome-wide linkage analysis in patients with cardiac laterality defects from a consanguineous family. The patients had combinations of defects that included dextrocardia, transposition of great arteries, double-outlet right ventricle, atrioventricular septal defects, and caval vein abnormalities. Sequencing of positional candidate genes identified mutations in NPHP4. We performed mutation analysis of NPHP4 in 146 unrelated patients with similar cardiac laterality defects. Forty-one percent of these patients also had laterality defects of the abdominal organs. We identified 8 additional missense variants that were absent or very rare in control subjects. To study the role of nphp4 in establishing L-R asymmetry, we used antisense morpholinos to knockdown nphp4 expression in zebrafish. Depletion of nphp4 disrupted L-R patterning as well as cardiac and gut laterality. Cardiac laterality defects were partially rescued by human NPHP4 mRNA, whereas mutant NPHP4 containing genetic variants found in patients failed to rescue. We show that nphp4 is involved in the formation of motile cilia in Kupffer's vesicle, which generate asymmetrical fluid flow necessary for normal L-R asymmetry. Conclusions: NPHP4 mutations are associated with cardiac laterality defects and heterotaxy. In zebrafish, nphp4 is essential for the development and function of Kupffer's vesicle cilia and is required for global L-R patterning

ADAMTS19-associated heart valve defects: Novel genetic variants consolidating a recognizable cardiac phenotype

Recently, ADAMTS19 was identified as a novel causative gene for autosomal recessive heart valve disease (HVD), affecting mainly the aortic and pulmonary valves. Exome sequencing and data repository (CentoMD) analyses were performed to identify patients with ADAMTS19 variants (two families). A third family was recognized based on cardiac phenotypic similarities and SNP array homozygosity. Three novel loss of function (LoF) variants were identified in six patients from three families. Clinically, all patients presented anomalies of the aortic/pulmonary valves, which included thickening of valve leaflets, stenosis and insufficiency. Three patients had (recurrent) subaortic membrane, suggesting that ADAMTS19 is the first gene identified related to discrete subaortic stenosis. One case presented a bi-commissural pulmonary valve. All patients displayed some degree of atrioventricular valve insufficiency. Other cardiac anomalies included atrial/ventricular septal defects, persistent ductus arteriosus, and mild dilated ascending aorta. Our findings confirm that biallelic LoF variants in ADAMTS19 are causative of a specific and recognizable cardiac phenotype. We recommend considering ADAMTS19 genetic testing in all patients with multiple semilunar valve abnormalities, particularly in the presence of subaortic membrane. ADAMTS19 screening in patients with semilunar valve abnormalities is needed to estimate the frequency of the HVD related phenotype, which might be not so rare

Lack of evidence for a causal role of CALR3 in monogenic cardiomyopathy

The pathogenicity of previously published disease-associated genes and variants is sometimes questionable. Large-scale, population-based sequencing studies have uncovered numerous false assignments of pathogenicity. Misinterpretation of sequence variants may have serious implications for the patients and families involved, as genetic test results are increasingly being used in medical decision making. In this study, we assessed the role of the calreticulin-3 gene (CALR3) in cardiomyopathy. CALR3 has been included in several cardiomyopathy gene panels worldwide. Its inclusion is based on a single publication describing two missense variants in patients with hypertrophic cardiomyopathy. In our national cardiomyopathy cohort (n = 6154), we identified 17 unique, rare heterozygous CALR3 variants in 48 probands. Overall, our patient cohort contained a significantly higher number of rare CALR3 variants compared to the ExAC population (p = 0.0036). However, after removing a potential Dutch founder variant, no statistically significant difference was found (p = 0.89). In nine probands, the CALR3 variant was accompanied by a disease-causing variant in another, well-known cardiomyopathy gene. In three families, the CALR3 variant did not segregate with the disease. Furthermore, we could not demonstrate calreticulin-3 protein expression in myocardial tissues at various ages. On the basis of these findings, it seems highly questionable that variants in CALR3 are a monogenic cause of cardiomyopathy

Androgen receptor profiling predicts prostate cancer outcome

Prostate cancer is the second most prevalent malignancy in men. Biomarkers for outcome prediction are urgently needed, so that high-risk patients could be monitored more closely postoperatively. To identify prognostic markers and to determine causal players in prostate cancer progression, we assessed changes in chromatin state during tumor development and progression. Based on this, we assessed genomewide androgen receptor/chromatin binding and identified a distinct androgen receptor/chromatin binding profile between primary prostate cancers and tumors with an acquired resistance to therapy. These differential androgen receptor/chromatin interactions dictated expression of a distinct gene signature with strong prognostic potential. Further refinement of the signature provided us with a concise list of nine genes that hallmark prostate cancer outcome in multiple independent validation series. In this report, we identified a novel gene expression signature for prostate cancer outcome through generation of multilevel genomic data on chromatin accessibility and transcriptional regulation and integration with publically available transcriptomic and clinical datastreams. By combining existing technologies, we propose a novel pipeline for biomarker discovery that is easily implementable in other fields of oncology