Outcome of adult patients with X-linked hypophosphatemia caused by PHEX gene mutations

X-linked hypophosphatemia (XLH) is the most common monogenic disorder causing hypophosphatemia. This case-note review documents the clinical features and the complications of treatment in 59 adults (19 male, 40 female) with XLH. XLH is associated with a large number of private mutations; 37 different mutations in the PHEX gene were identified in this cohort, 14 of which have not been previously reported. Orthopaedic involvement requiring surgical intervention (osteotomy) was frequent. Joint replacement and decompressive laminectomy were observed in those older than 40 years. Dental disease (63%), nephrocalcinosis (42%), and hearing impairment (14%) were also common. The rarity of the disease and the large number of variants make it difficult to discern specific genotype-phenotype relationships. A new treatment, an anti-FGF23 antibody, that may affect the natural history of the disease is currently being investigated in clinical trials

The microbial production of polyhydroxyalkanoates from waste polystyrene fragments attained using oxidative degradation

© 2018 The Authors. Published by MDPI. This is an open access article available under a Creative Commons licence. The published version can be accessed at the following link on the publisher’s website: https://doi.org/10.3390/polym10090957Excessive levels of plastic waste in our oceans and landfills indicate that there is an abundance of potential carbon sources with huge economic value being neglected. These waste plastics, through biological fermentation, could offer alternatives to traditional petrol-based plastics. Polyhydroxyalkanoates (PHAs) are a group of plastics produced by some strains of bacteria that could be part of a new generation of polyester materials that are biodegradable, biocompatible, and, most importantly, non-toxic if discarded. This study introduces the use of prodegraded high impact and general polystyrene (PS0). Polystyrene is commonly used in disposable cutlery, CD cases, trays, and packaging. Despite these applications, some forms of polystyrene PS remain financially and environmentally expensive to send to landfills. The prodegraded PS0 waste plastics used were broken down at varied high temperatures while exposed to ozone. These variables produced PS flakes (PS1–3) and a powder (PS4) with individual acid numbers. Consequently, after fermentation, different PHAs and amounts of biomass were produced. The bacterial strain, Cupriavidus necator H16, was selected for this study due to its well-documented genetic profile, stability, robustness, and ability to produce PHAs at relatively low temperatures. The accumulation of PHAs varied from 39% for prodegraded PS0 in nitrogen rich media to 48% (w/w) of dry biomass with the treated PS. The polymers extracted from biomass were analyzed using nuclear magnetic resonance (NMR) and electrospray ionization tandem mass spectrometry (ESI-MS/MS) to assess their molecular structure and properties. In conclusion, the PS0–3 specimens were shown to be the most promising carbon sources for PHA biosynthesis; with 3-hydroxybutyrate and up to 12 mol % of 3-hydroxyvalerate and 3-hydroxyhexanoate co-monomeric units generated

Asymmetric Distribution of Extreme Values of Cubic LL-functions at s=1s=1

We investigate the distribution of values of cubic Dirichlet L-functions at s=1. Following ideas of Granville and Soundararajan for quadratic L-functions, we model the distribution of L(1,χ) by the distribution of random Euler products L(1,X) for certain family of random variables X(p) attached to each prime. We obtain a description of the proportion of |L(1,χ)| that are larger or that are smaller than a given bound, and yield more light into the Littlewood bounds. Unlike the quadratic case, there is an asymmetry between lower and upper bounds for the cubic case, and small values are less probable than large values

Genetic risk prediction of atrial fibrillation

Background—Atrial fibrillation (AF) has a substantial genetic basis. Identification of individuals at greatest AF risk could minimize the incidence of cardioembolic stroke. Methods—To determine whether genetic data can stratify risk for development of AF, we examined associations between AF genetic risk scores and incident AF in five prospective studies comprising 18,919 individuals of European ancestry. We examined associations between AF genetic risk scores and ischemic stroke in a separate study of 509 ischemic stroke cases (202 cardioembolic [40%]) and 3,028 referents. Scores were based on 11 to 719 common variants (≥5%) associated with AF at P-values ranging from <1x10-3 to <1x10-8 in a prior independent genetic association study. Results—Incident AF occurred in 1,032 (5.5%) individuals. AF genetic risk scores were associated with new-onset AF after adjusting for clinical risk factors. The pooled hazard ratio for incident AF for the highest versus lowest quartile of genetic risk scores ranged from 1.28 (719 variants; 95%CI, 1.13-1.46; P=1.5x10-4) to 1.67 (25 variants; 95%CI, 1.47-1.90; P=9.3x10-15). Discrimination of combined clinical and genetic risk scores varied across studies and scores (maximum C statistic, 0.629-0.811; maximum ΔC statistic from clinical score alone, 0.009-0.017). AF genetic risk was associated with stroke in age- and sex-adjusted models. For example, individuals in the highest versus lowest quartile of a 127-variant score had a 2.49-fold increased odds of cardioembolic stroke (95%CI, 1.39-4.58; P=2.7x10-3). The effect persisted after excluding individuals (n=70) with known AF (odds ratio, 2.25; 95%CI, 1.20-4.40; P=0.01). Conclusions—Comprehensive AF genetic risk scores were associated with incident AF beyond associations for clinical AF risk factors, though offered small improvements in discrimination. AF genetic risk was also associated with cardioembolic stroke in age- and sex-adjusted analyses. Efforts are warranted to determine whether AF genetic risk may improve identification of subclinical AF or help distinguish between stroke mechanisms

Obesity as predictive factor of periodontal therapy clinical outcomes: A cohort study

AIM: The study aim was to investigate the predictive role of obesity on clinical response following non-surgical periodontal therapy in individuals with severe periodontitis. METHODS: 57 BMI obese and 58 BMI normal non-smoker adults with periodontitis (defined as probing pocket depths (PPD) of ≥5 mm and alveolar bone loss of >30% with >50% of the teeth affected) received non-surgical periodontal therapy. Periodontal status was based upon PPD, clinical attachment level(CAL), and full mouth bleeding score(FMBS). Mean PPD, percentage sites PPD>4mm, percentage sites PPD>5mm, and FMBS at 2 and 6 months were outcome variables. Propensity score analysis was used to assess the effect of obesity on outcome variables after adjusting for confounders. RESULTS: Statistically significant higher clinical measures (mean PPD, mean percentage of sites with PPD>4mm, mean percentage of sites with PPD>5mm, and FMBS) were observed in the obese group than the normal group at baseline, 2 and 6 months after therapy(p4mm(p5mm(p<0.05), and FMBS (p<0.01), independent of age, gender, ethnicity or plaque levels. CONCLUSIONS: Obesity compared to normal BMI status was an independent predictor of poorer response following non-surgical periodontal therapy

Evaluation of muscle strength and motor abilities in children with type II and III spinal muscle atrophy treated with valproic acid

<p>Abstract</p> <p>Background</p> <p>Spinal muscular atrophy (SMA) is an autosomal recessive disorder that affects the motoneurons of the spinal anterior horn, resulting in hypotonia and muscle weakness. The disease is caused by deletion or mutation in the telomeric copy of <it>SMN </it>gene (<it>SMN1</it>) and clinical severity is in part determined by the copy number of the centromeric copy of the <it>SMN </it>gene (<it>SMN2</it>). The <it>SMN2 </it>mRNA lacks exon 7, resulting in a production of lower amounts of the full-length SMN protein. Knowledge of the molecular mechanism of diseases has led to the discovery of drugs capable of increasing SMN protein level through activation of <it>SMN2 </it>gene. One of these drugs is the valproic acid (VPA), a histone deacetylase inhibitor.</p> <p>Methods</p> <p>Twenty-two patients with type II and III SMA, aged between 2 and 18 years, were treated with VPA and were evaluated five times during a one-year period using the Manual Muscle Test (Medical Research Council scale-MRC), the Hammersmith Functional Motor Scale (HFMS), and the Barthel Index.</p> <p>Results</p> <p>After 12 months of therapy, the patients did not gain muscle strength. The group of children with SMA type II presented a significant gain in HFMS scores during the treatment. This improvement was not observed in the group of type III patients. The analysis of the HFMS scores during the treatment period in the groups of patients younger and older than 6 years of age did not show any significant result. There was an improvement of the daily activities at the end of the VPA treatment period.</p> <p>Conclusion</p> <p>Treatment of SMA patients with VPA may be a potential alternative to alleviate the progression of the disease.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov: <a href="http://www.clinicaltrials.gov/ct2/show/NCT01033331">NCT01033331</a></p

Large-scale analyses of common and rare variants identify 12 new loci associated with atrial fibrillation

Atrial fibrillation affects more than 33 million people worldwide and increases the risk of stroke, heart failure, and death. Fourteen genetic loci have been associated with atrial fibrillation in European and Asian ancestry groups. To further define the genetic basis of atrial fibrillation, we performed large-scale, trans-ancestry meta-analyses of common and rare variant association studies. The genome-wide association studies (GWAS) included 17,931 individuals with atrial fibrillation and 115,142 referents; the exome-wide association studies (ExWAS) and rare variant association studies (RVAS) involved 22,346 cases and 132,086 referents. We identified 12 new genetic loci that exceeded genome-wide significance, implicating genes involved in cardiac electrical and structural remodeling. Our results nearly double the number of known genetic loci for atrial fibrillation, provide insights into the molecular basis of atrial fibrillation, and may facilitate the identification of new potential targets for drug discovery

Signal-averaged P wave analysis for delineation of interatrial conduction – Further validation of the method

<p>Abstract</p> <p>Background</p> <p>The study was designed to investigate the effect of different measuring methodologies on the estimation of P wave duration. The recording length required to ensure reproducibility in unfiltered, signal-averaged P wave analysis was also investigated. An algorithm for automated classification was designed and its reproducibility of manual P wave morphology classification investigated.</p> <p>Methods</p> <p>Twelve-lead ECG recordings (1 kHz sampling frequency, 0.625 <it>μ</it>V resolution) from 131 healthy subjects were used. Orthogonal leads were derived using the inverse Dower transform. Magnification (100 times), baseline filtering (0.5 Hz high-pass and 50 Hz bandstop filters), signal averaging (10 seconds) and bandpass filtering (40–250 Hz) were used to investigate the effect of methodology on the estimated P wave duration. Unfiltered, signal averaged P wave analysis was performed to determine the required recording length (6 minutes to 10 s) and the reproducibility of the P wave morphology classification procedure. Manual classification was carried out by two experts on two separate occasions each. The performance of the automated classification algorithm was evaluated using the joint decision of the two experts (i.e., the consensus of the two experts).</p> <p>Results</p> <p>The estimate of the P wave duration increased in each step as a result of magnification, baseline filtering and averaging (100 ± 18 vs. 131 ± 12 ms; P < 0.0001). The estimate of the duration of the bandpass-filtered P wave was dependent on the noise cut-off value: 119 ± 15 ms (0.2 <it>μ</it>V), 138 ± 13 ms (0.1 <it>μ</it>V) and 143 ± 18 ms (0.05 <it>μ</it>V). (P = 0.01 for all comparisons).</p> <p>The mean errors associated with the P wave morphology parameters were comparable in all segments analysed regardless of recording length (95% limits of agreement within 0 ± 20% (mean ± SD)). The results of the 6-min analyses were comparable to those obtained at the other recording lengths (6 min to 10 s).</p> <p>The intra-rater classification reproducibility was 96%, while the interrater reproducibility was 94%. The automated classification algorithm agreed with the manual classification in 90% of the cases.</p> <p>Conclusion</p> <p>The methodology used has profound effects on the estimation of P wave duration, and the method used must therefore be validated before any inferences can be made about P wave duration. This has implications in the interpretation of multiple studies where P wave duration is assessed, and conclusions with respect to normal values are drawn.</p> <p>P wave morphology and duration assessed using unfiltered, signal-averaged P wave analysis have high reproducibility, which is unaffected by the length of the recording. In the present study, the performance of the proposed automated classification algorithm, providing total reproducibility, showed excellent agreement with manually defined P wave morphologies.</p

GWAS of QRS Duration Identifies New Loci Specific to Hispanic/Latino Populations

BACKGROUND: The electrocardiographically quantified QRS duration measures ventricular depolarization and conduction. QRS prolongation has been associated with poor heart failure prognosis and cardiovascular mortality, including sudden death. While previous genome-wide association studies (GWAS) have identified 32 QRS SNPs across 26 loci among European, African, and Asian-descent populations, the genetics of QRS among Hispanics/Latinos has not been previously explored. METHODS: We performed a GWAS of QRS duration among Hispanic/Latino ancestry populations (n = 15,124) from four studies using 1000 Genomes imputed genotype data (adjusted for age, sex, global ancestry, clinical and study-specific covariates). Study-specific results were combined using fixed-effects, inverse variance-weighted meta-analysis. RESULTS: We identified six loci associated with QRS (P CONCLUSIONS: Our QRS duration GWAS, the first in Hispanic/Latino populations, identified two new loci, underscoring the utility of extending large scale genomic studies to currently under-examined populations