Diabetic foot assessment using skin impedance in a custom made sensor-sock

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Transethnic Genome-Wide Association Study Provides Insights in the Genetic Architecture and Heritability of Long QT Syndrome

BACKGROUND: Long QT syndrome (LQTS) is a rare genetic disorder and a major preventable cause of sudden cardiac death in the young. A causal rare genetic variant with large effect size is identified in up to 80% of probands (genotype positive) and cascade family screening shows incomplete penetrance of genetic variants. Furthermore, a proportion of cases meeting diagnostic criteria for LQTS remain genetically elusive despite genetic testing of established genes (genotype negative). These observations raise the possibility that common genetic variants with small effect size contribute to the clinical picture of LQTS. This study aimed to characterize and quantify the contribution of common genetic variation to LQTS disease susceptibility. METHODS: We conducted genome-wide association studies followed by transethnic meta-analysis in 1656 unrelated patients with LQTS of European or Japanese ancestry and 9890 controls to identify susceptibility single nucleotide polymorphisms. We estimated the common variant heritability of LQTS and tested the genetic correlation between LQTS susceptibility and other cardiac traits. Furthermore, we tested the aggregate effect of the 68 single nucleotide polymorphisms previously associated with the QT-interval in the general population using a polygenic risk score. RESULTS: Genome-wide association analysis identified 3 loci associated with LQTS at genome-wide statistical significance (P&lt;5×10-8) near NOS1AP, KCNQ1, and KLF12, and 1 missense variant in KCNE1(p.Asp85Asn) at the suggestive threshold (P&lt;10-6). Heritability analyses showed that ≈15% of variance in overall LQTS susceptibility was attributable to common genetic variation (h2SNP 0.148; standard error 0.019). LQTS susceptibility showed a strong genome-wide genetic correlation with the QT-interval in the general population (rg=0.40; P=3.2×10-3). The polygenic risk score comprising common variants previously associated with the QT-interval in the general population was greater in LQTS cases compared with controls (P&lt;10-13), and it is notable that, among patients with LQTS, this polygenic risk score was greater in patients who were genotype negative compared with those who were genotype positive (P&lt;0.005). CONCLUSIONS: This work establishes an important role for common genetic variation in susceptibility to LQTS. We demonstrate overlap between genetic control of the QT-interval in the general population and genetic factors contributing to LQTS susceptibility. Using polygenic risk score analyses aggregating common genetic variants that modulate the QT-interval in the general population, we provide evidence for a polygenic architecture in genotype negative LQTS.</p

Multi-trait analysis characterizes the genetics of thyroid function and identifies causal associations with clinical implications

To date only a fraction of the genetic footprint of thyroid function has been clarified. We report a genome-wide association study meta-analysis of thyroid function in up to 271,040 individuals of European ancestry, including reference range thyrotropin (TSH), free thyroxine (FT4), free and total triiodothyronine (T3), proxies for metabolism (T3/FT4 ratio) as well as dichotomized high and low TSH levels. We revealed 259 independent significant associations for TSH (61% novel), 85 for FT4 (67% novel), and 62 novel signals for the T3 related traits. The loci explained 14.1%, 6.0%, 9.5% and 1.1% of the total variation in TSH, FT4, total T3 and free T3 concentrations, respectively. Genetic correlations indicate that TSH associated loci reflect the thyroid function determined by free T3, whereas the FT4 associations represent the thyroid hormone metabolism. Polygenic risk score and Mendelian randomization analyses showed the effects of genetically determined variation in thyroid function on various clinical outcomes, including cardiovascular risk factors and diseases, autoimmune diseases, and cancer. In conclusion, our results improve the understanding of thyroid hormone physiology and highlight the pleiotropic effects of thyroid function on various diseases

Cerebral small vessel disease genomics and its implications across the lifespan

White matter hyperintensities (WMH) are the most common brain-imaging feature of cerebral small vessel disease (SVD), hypertension being the main known risk factor. Here, we identify 27 genome-wide loci for WMH-volume in a cohort of 50,970 older individuals, accounting for modification/confounding by hypertension. Aggregated WMH risk variants were associated with altered white matter integrity (p = 2.5×10-7) in brain images from 1,738 young healthy adults, providing insight into the lifetime impact of SVD genetic risk. Mendelian randomization suggested causal association of increasing WMH-volume with stroke, Alzheimer-type dementia, and of increasing blood pressure (BP) with larger WMH-volume, notably also in persons without clinical hypertension. Transcriptome-wide colocalization analyses showed association of WMH-volume with expression of 39 genes, of which four encode known drug targets. Finally, we provide insight into BP-independent biological pathways underlying SVD and suggest potential for genetic stratification of high-risk individuals and for genetically-informed prioritization of drug targets for prevention trials.Peer reviewe

Enhancing rare variant interpretation in inherited arrhythmias through quantitative analysis of consortium disease cohorts and population controls.

PURPOSE: Stringent variant interpretation guidelines can lead to high rates of variants of uncertain significance (VUS) for genetically heterogeneous disease like long QT syndrome (LQTS) and Brugada syndrome (BrS). Quantitative and disease-specific customization of American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines can address this false negative rate. METHODS: We compared rare variant frequencies from 1847 LQTS (KCNQ1/KCNH2/SCN5A) and 3335 BrS (SCN5A) cases from the International LQTS/BrS Genetics Consortia to population-specific gnomAD data and developed disease-specific criteria for ACMG/AMP evidence classes-rarity (PM2/BS1 rules) and case enrichment of individual (PS4) and domain-specific (PM1) variants. RESULTS: Rare SCN5A variant prevalence differed between European (20.8%) and Japanese (8.9%) BrS patients (p = 5.7 × 10-18) and diagnosis with spontaneous (28.7%) versus induced (15.8%) Brugada type 1 electrocardiogram (ECG) (p = 1.3 × 10-13). Ion channel transmembrane regions and specific N-terminus (KCNH2) and C-terminus (KCNQ1/KCNH2) domains were characterized by high enrichment of case variants and >95% probability of pathogenicity. Applying the customized rules, 17.4% of European BrS and 74.8% of European LQTS cases had (likely) pathogenic variants, compared with estimated diagnostic yields (case excess over gnomAD) of 19.2%/82.1%, reducing VUS prevalence to close to background rare variant frequency. CONCLUSION: Large case-control data sets enable quantitative implementation of ACMG/AMP guidelines and increased sensitivity for inherited arrhythmia genetic testing

Development and Assessment of Electrodes and Instrumentation for Plantar Skin Impedance Measurements

This thesis describes the development and test of electrodes and electrode setup for plantar bioimpedance measurements. Several electrodes of different sizes, geometry and materials were tested to find one suited for plantar skin impedance measurements. With three electrodes, customized instrumentation and measurement techniques, a test study was performed on ten participants. The results showed that a bipolar Ag ring electrode was best suited for plantar skin measurements

Diabetic foot assessment using skin impedance in a custom made sensor-sock

Diabetic peripheral neuropathy (DPN) may lead to several changes in the skin, and some of these may influence the skin impedance spectrum. In the present study we have developed a prototype solution for skin impedance spectroscopy at selected skin sites (big toe pulp, heel and toe ball) that was tested in a pilot study on five patients with DPN and five healthy controls. At the big toe, most of the controls had markedly lower impedance than the DPN group, especially in the range of 1-100 kHz. The separation between the groups seems to be weaker at the heel and weakest at the toeball. The results may indicate that monitoring of the skin impedance spectrum may be a method for detection of skin changes associated with DPN, encouraging further studies with the big toe sensor in particular

A potato model intercomparison across varying climates and productivity levels

A potato crop multimodel assessment was conducted to quantify variation among models and evaluate responses to climate change. Nine modeling groups simulated agronomic and climatic responses at low-input (Chinoli, Bolivia and Gisozi, Burundi)- and high-input (Jyndevad, Denmark and Washington, United States) management sites. Two calibration stages were explored, partial (P1), where experimental dry matter data were not provided, and full (P2). The median model ensemble response outperformed any single model in terms of replicating observed yield across all locations. Uncertainty in simulated yield decreased from 38% to 20% between P1 and P2. Model uncertainty increased with interannual variability, and predictions for all agronomic variables were significantly different from one model to another (P < 0.001). Uncertainty averaged 15% higher for low- vs. high-input sites, with larger differences observed for evapotranspiration (ET), nitrogen uptake, and water use efficiency as compared to dry matter. A minimum of five partial, or three full, calibrated models was required for an ensemble approach to keep variability below that of common field variation. Model variation was not influenced by change in carbon dioxide (C), but increased as much as 41% and 23% for yield and ET, respectively, as temperature (T) or rainfall (W) moved away from historical levels. Increases in T accounted for the highest amount of uncertainty, suggesting that methods and parameters for T sensitivity represent a considerable unknown among models. Using median model ensemble values, yield increased on average 6% per 100-ppm C, declined 4.6% per °C, and declined 2% for every 10% decrease in rainfall (for nonirrigated sites). Differences in predictions due to model representation of light utilization were significant (P < 0.01). These are the first reported results quantifying uncertainty for tuber/root crops and suggest modeling assessments of climate change impact on potato may be improved using an ensemble approach

A potato model intercomparison across varying climates and productivity levels

A potato crop multi-model assessment was conducted to quantify variation among models and evaluate responses to climate change. Nine modeling groups simulated agronomic and climatic responses at low- (Chinoli, Bolivia and Gisozi, Burundi) and high- (Jyndevad, Denmark and Washington, United States) input management sites. Two calibration stages were explored, partial (P1), where experimental dry matter data were not provided, and full (P2). The median model ensemble response outperformed any single model in terms of replicating observed yield across all locations. Uncertainty in simulated yield decreased from 38% to 20% between P1 and P2. Model uncertainty increased with inter-annual variability, and predictions for all agronomic variables were significantly different from one model to another (p < 0.001). Uncertainty averaged 15% higher for low- versus high- input sites, with larger differences observed for evapotranspiration (ET), nitrogen uptake, and water use efficiency as compared to dry matter. A minimum of five partial, or three full, calibrated models was required for an ensemble approach to keep variability below that of common field variation. Model variation was not influenced by change in carbon dioxide (C), but increased as much as 41 and 23% for yield and ET respectively as temperature (T) or rainfall (W) moved away from historical levels. Increases in T accounted for the highest amount of uncertainty, suggesting that methods and parameters for T sensitivity represent a considerable unknown among models. Using median model ensemble values, yield increased on average 6% per 100-ppm C, declined 4.6% per °C, and declined 2% for every 10% decrease in rainfall (for non-irrigated sites). Differences in predictions due to model representation of light utilization were significant (p < 0.01). These are the first reported results quantifying uncertainty for tuber/root crops and suggest modeling assessments of climate change impact on potato may be improved using an ensemble approach.status: publishe

Irritable Bowel Syndrome and Microscopic Colitis: A Systematic Review and Meta-Analysis

Patients with microscopic colitis and patients with irritable bowel syndrome (IBS) present with similar symptoms. We examined the association between IBS and microscopic colitis in a systematic review and meta-analysis.We searched the medical literature to identify cross-sectional surveys or case-control studies reporting the association between microscopic colitis and IBS in 50 or more unselected adult patients. We recorded the prevalence of IBS symptoms in patients with histologically confirmed microscopic colitis, or the prevalence of histologically confirmed microscopic colitis in patients with IBS. Data were pooled using a random-effects model; the association between microscopic colitis and IBS was summarized using an odds ratio (OR) with a 95% confidence interval (CI).The search strategy identified 3926 citations, of which 10 were eligible for our analysis. The pooled prevalence of IBS in patients with microscopic colitis was 33.4% (95% CI, 31.5%-40.6%), but was not significantly higher in patients with microscopic colitis than in patients with diarrhea (OR, 1.39; 95% CI, 0.43-4.47). In 3 cross-sectional surveys, the pooled OR for microscopic colitis in participants with IBS, compared with other patients with diarrhea, was 0.68 (95% CI, 0.44-1.04). In 4 case-control studies the prevalence of IBS in patients with microscopic colitis was significantly higher than in asymptomatic controls (OR, 5.16; 95% CI, 1.32-20.2).Based on a meta-analysis, one third of patients with microscopic colitis reported symptoms compatible with IBS, but the prevalence of IBS was no higher than in other patients with diarrhea. The odds of microscopic colitis were no higher in patients with IBS compared with other patients with diarrhea. The value of routine colonoscopy and biopsy to exclude microscopic colitis in patients with typical IBS symptoms, unless other risk factors or alarm symptoms are present, remains uncertain