Diffuse Sclerosing Papillary Carcinoma In A Pediatric Patient With Intrauterine Diagnostic Xray Exposure

Objective: The relationship between occurrence of childhood cancer and intrauterine exposure to radiation is well known. We describe a case of diffuse sclerosing papillary carcinoma (PTC) in a pediatric patient exposed to diagnostic radiation in utero. Methods: Clinical presentation, including radiation history and outcome, was reported. Case Presentation: A 14 year old male was referred for a thyroid cancer consultation in 2008. His history was notable for a rapidly growing thyroid mass during the preceding 3 months and in utero exposure to radiation, in the form of multiple xrays and CT scans, at 12 weeks gestation as a result of maternal multiple trauma due to a car accident. A total thyroidectomy with bilateral central, level 7 and right modified neck dissection for a rapidly growing thyroid mass was performed. Pathology revealed multifocal, bilateral, moderately differentiated, diffuse sclerosing PTC 8.6 em in greatest dimension. The tumor was not encapsulated, with vascular invasion and extensive extrathyroidal extension. Metastases were positive in 32 of 36 lymph nodes sampled. Post-operative unstimulated thyroglobulin (Tg) by RIA and Tg antibody (TgAb) were 137 (0-39 ng/mL) and 4183 (0- 100 IU/mL), respectively. Ultrasound (US), PET/CT and post I-131 treatment scan revealed abnormal nodes but no distant metastases. To date, he has had an additional right neck dissection for poorly differentiated PTC lymph node metastases, a total of 340 mCi ofl-131, and has persistently positive unstimulated Tg and TgAb at 9.2 (/mL) and 36 ( Discussion: Diffuse sclerosing PTC occurred in this pediatric patient exposed to diagnostic radiation in utero. His clinical course was notable for locally aggressive behavior of the PTC and biochemically persistent disease. A causal relationship between the timing and quantity of the radiation exposure and the development of a rare variant of PTC in this patient was suspected. Conclusion: The relationship between radiation exposure and PTC is well known. Case control studies have documented an increased risk of childhood cancer in those exposed to radiation over 10mSv in utero. Although radiation exposure to the developing fetus rarely occurs, consideration should be given for close monitoring of in utero radiation exposed patients for the development of PTC

Correcting for heterogeneity in real-time epidemiological indicators

Auxiliary data sources have become increasingly important in epidemiological surveillance, as they are often available at a finer spatial and temporal resolution, larger coverage, and lower latency than traditional surveillance signals. We describe the problem of spatial and temporal heterogeneity in these signals derived from these data sources, where spatial and/or temporal biases are present. We present a method to use a ``guiding'' signal to correct for these biases and produce a more reliable signal that can be used for modeling and forecasting. The method assumes that the heterogeneity can be approximated by a low-rank matrix and that the temporal heterogeneity is smooth over time. We also present a hyperparameter selection algorithm to choose the parameters representing the matrix rank and degree of temporal smoothness of the corrections. In the absence of ground truth, we use maps and plots to argue that this method does indeed reduce heterogeneity. Reducing heterogeneity from auxiliary data sources greatly increases their utility in modeling and forecasting epidemics

Antiepileptic Drug Monotherapy: The Initial Approach in Epilepsy Management

Antiepileptic drug (AED) monotherapy is the preferred initial management approach in epilepsy care, since most patients may be successfully managed with the first or second monotherapy utilized. This article reviews the rationale and evidence supporting preferential use of monotherapy when possible and guidelines for initiating and successfully employing AED monotherapy. Suggested approaches to consider when patients fail monotherapy include substituting a new AED monotherapy, initiating chronic maintenance AED polytherapy, or pursuit of non-pharmacologic treatments such as epilepsy surgery or vagus nerve stimulation. Reducing AED polytherapy to monotherapy frequently reduces the burden of adverse effects and may also improve seizure control. AED monotherapy remains the optimal approach for managing most patients with epilepsy

Pathogenic Variants in Fucokinase Cause a Congenital Disorder of Glycosylation

FUK encodes fucokinase, the only enzyme capable of converting L-fucose to fucose-1-phosphate, which will ultimately be used for synthesizing GDP-fucose, the donor substrate for all fucosyltransferases. Although it is essential for fucose salvage, this pathway is thought to make only a minor contribution to the total amount of GDP-fucose. A second pathway, the major de novo pathway, involves conversion of GDP-mannose to GDP-fucose. Here we describe two unrelated individuals who have pathogenic variants in FUK and who presented with severe developmental delays, encephalopathy, intractable seizures, and hypotonia. The first individual was compound heterozygous for c.667T>C (p.Ser223Pro) and c.2047C>T (p.Arg683Cys), and the second individual was homozygous for c.2980A>C (p.Lys994Gln). Skin fibroblasts from the first individual confirmed the variants as loss of function and showed significant decreases in total GDP-[3H] fucose and [3H] fucose-1-phosphate. There was also a decrease in the incorporation of [5,6-3H]-fucose into fucosylated glycoproteins. Lys994 has previously been shown to be an important site for ubiquitin conjugation. Here, we show that loss-of-function variants in FUK cause a congenital glycosylation disorder characterized by a defective fucose-salvage pathway

The effect of dietary taurine and its potential biosynthesis on juvenile grey mullet (Mugil cephalus) performance

The grey mullet is a catadromous species that spawns in the taurine-rich seawater environment, followed by the young fish generally migrating to less saline, low taurine waters during the larva-juvenile transition. Consequently, this study aimed to (1) determines whether there is a dietary taurine requirement in juvenile grey mullet for enhanced growth and (2) the potential for taurine biosynthesis. The experimental system consisted of sixteen 400-l V-tanks, where filtered, UV-treated ambient seawater (40 ‰) entered the bottom of the tanks at a rate of 7 tank exchanges/day. This allowed the testing of four 1 mm pelleted diets (0, 0.5, 1.0, and 2.0% taurine DW diet) in replicates of 4 tanks/treatment for 58 days. Grey mullet juveniles demonstrated (P<0.05) a specific requirement for a 0.5% taurine DW diet for improved growth. Fish fed the taurine diets displayed populations with a markedly (P < 0.05) higher average number of surviving fish (23.4±1.1) of moderately sized (10- 20 g) cohorts than smaller (< 10 g) individuals (12.5±1.1). In contrast, the fish fed the taurine control (0% taurine) exhibited similar average numbers of small and moderate sized fish (18.0±3.6-20.0±4.1). Dietary taurine accumulated highly (P<0.05) in the muscles in a dose dependent manner but less so (P<0.05) in eyes, and liver. The gene expression of liver cysteine sulfinic acid decarboxylase (CSD) exhibited an upregulation (P<0.05) with taurine diets from 0 to 1% but was down regulated (P<0.05) in fish fed the 2% taurine DW diet

Onset of efficacy and adverse events during Cenobamate titration period

Cenobamate; Drug-resistant epilepsy; SeizuresCenobamato; Epilepsia resistente a los medicamentos; ConvulsionesCenobamat; Epilèpsia resistent a medicaments; ConvulsionsObjectives Cenobamate is an antiseizure medication (ASM) approved in Europe as adjunctive therapy for adults with inadequately controlled focal seizures. This post hoc analysis reports onset of efficacy and characterizes time to onset, duration, and severity of the most common treatment-emergent adverse events (TEAEs) during cenobamate titration. Materials & Methods Adult patients with uncontrolled focal seizures taking 1 to 3 concomitant ASMs were randomized to receive adjunctive cenobamate or placebo (double-blind studies C013 and C017) or cenobamate (open-label study C021). Outcome assessments included efficacy (median percentage change in seizure frequency and onset [studies C013 and C017]) and safety (onset, duration, and severity of TEAEs [all studies]). Results Onset of efficacy was observed by Weeks 1 to 4 of titration in studies C013 and C017 which used a faster titration schedule than study CO21. In study C013, the median percentage seizure frequency reduction was 36.7% in patients receiving cenobamate versus 16.3% in those taking placebo (p = .002); in study C017, significant differences in seizure frequency emerged in Week 1 and continued throughout titration between all cenobamate groups and placebo (p < .001). The most commonly reported TEAEs were somnolence, dizziness, fatigue, and headache, with first onset of each reported as early as Week 1; however, the majority resolved. Conclusions Reductions in seizure frequency occurred during titration with initial efficacy observed prior to reaching the target dose. These reductions were regarded as clinically meaningful because they may indicate early efficacy at lower doses than previously expected and had a considerable impact on patient quality of life. Long-term treatment with adjunctive cenobamate was generally safe and well-tolerated.The double-blind studies and open-label study were funded by SK Life Science, Inc. (Paramus, NJ, USA). Study data were pooled and analyzed by Angelini S.p.a. Nicole Day, PhD, of MedVal Scientific Information Services, LLC (Princeton, NJ, USA) provided medical writing assistance, funded by Angelini S.p.a. The manuscript was prepared according to the International Society for Medical Publication Professionals' “Good Publication Practice for Communicating Company-Sponsored Medical Research: GPP3.

Allele-specific NKX2-5 binding underlies multiple genetic associations with human electrocardiographic traits.

The cardiac transcription factor (TF) gene NKX2-5 has been associated with electrocardiographic (EKG) traits through genome-wide association studies (GWASs), but the extent to which differential binding of NKX2-5 at common regulatory variants contributes to these traits has not yet been studied. We analyzed transcriptomic and epigenomic data from induced pluripotent stem cell-derived cardiomyocytes from seven related individuals, and identified ~2,000 single-nucleotide variants associated with allele-specific effects (ASE-SNVs) on NKX2-5 binding. NKX2-5 ASE-SNVs were enriched for altered TF motifs, for heart-specific expression quantitative trait loci and for EKG GWAS signals. Using fine-mapping combined with epigenomic data from induced pluripotent stem cell-derived cardiomyocytes, we prioritized candidate causal variants for EKG traits, many of which were NKX2-5 ASE-SNVs. Experimentally characterizing two NKX2-5 ASE-SNVs (rs3807989 and rs590041) showed that they modulate the expression of target genes via differential protein binding in cardiac cells, indicating that they are functional variants underlying EKG GWAS signals. Our results show that differential NKX2-5 binding at numerous regulatory variants across the genome contributes to EKG phenotypes