Refractive Index-Based Terahertz Sensor Using Graphene for Material Characterization.

In this paper, a graphene-based THz metamaterial has been designed and characterized for use in sensing various refractive index profiles. The proposed single-band THz sensor was constructed using a graphene-metal hybridized periodic metamaterial wherein the unit cell had a footprint of 1.395λeff × 1.395λeff and resonated at 4.4754 THz. The realized peak absorption was 98.88% at 4.4754 THz. The sensitivity of the proposed metamaterial sensor was estimated using the absorption characteristics of the unit cell. The performance of the sensor was analyzed under two different categories, viz. the random dielectric loading and chemical analytes, based on the refractive index. The proposed THz sensor offered a peak sensitivity of 22.75 GHz/Refractive Index Unit (RIU) for the various sample loadings. In addition, the effect of the sample thickness on the sensor performance was analyzed and the results were presented. From the results, it can be inferred that the proposed metamaterial THz sensor that was based on a refractive index is suitable for THz sensing applications.

Assessing appropriateness of pediatric emergency department visits: is it even possible?

OBJECTIVES: Numerous studies reported on the frequency of, and factors associated with inappropriate or unnecessary emergency department (ED) visits using clinician judgment as the gold standard of appropriateness. This study evaluated the reliability of clinician judgment for assessing appropriateness of pediatric ED visit. METHODS: We conducted a retrospective cohort study comparing 3 clinicians' determination of ED visit appropriateness with and without guidance from a three-question structured algorithm. We used a cohort of scheduled ED return visits deemed appropriate by the index treating clinician between May 1, 2012, and April 30, 2013. We measured the level of agreement among three clinician investigators with and without use of the structured algorithm. RESULTS: A total of 207 scheduled ED return visits were reviewed by the primary clinician reviewer who agreed with the index treating clinician for 79/207 visits (38.2%). Among a random subset of 90 return visits reviewed by all three clinicians, agreement was 67% with a Fleiss' Kappa of 0.30 (0.17-0.44). Using a three-question algorithm based on objective criteria, agreement with the index treating provider increased to 115/207 (55.6%). CONCLUSIONS: Although an important contributor to pediatric ED overcrowding, unnecessary or inappropriate visits are difficult to identify. We demonstrated poor reliability of clinician judgment to determine appropriateness of ED return visits, likely due to variability in clinical decision-making and risk-tolerance, social and systems factors impacting access and use of health care. We recommend that future studies evaluating the appropriateness of ED use standardized, objective criteria rather than clinician judgment alone.

Optimization of a preparative multimodal ion exchange step for purification of a potential malaria vaccine.

In 2000 the implementation of quality by design (QbD) was introduced by the Food and Drug Administration (FDA) and described in the ICH Q8, Q9 and Q10 guidelines. Since that time, systematic optimization strategies for purification of biopharmaceuticals have gained a more important role in industrial process development. In this investigation, the optimization strategy was carried out by adopting design of experiments (DoE) in small scale experiments. A combination method comprising a desalting and a multimodal ion exchange step was used for the experimental runs via the chromatographic system ÄKTA™ avant. The multimodal resin Capto™ adhere was investigated as an alternative to conventional ion exchange and hydrophobic interaction resins for the intermediate purification of the potential malaria vaccine D1M1. The ligands, used in multimodal chromatography, interact with the target molecule in different ways. The multimodal functionality includes the binding of proteins in spite of the ionic strength of the loading material. The target protein binds at specific salt conditions and can be eluted by a step gradient decreasing the pH value and reducing the ionic strength. It is possible to achieve a maximized purity and recovery of the product because degradation products and other contaminants do not bind at specific salt concentrations at which the product still binds to the ligands.

Hypomorphic temperature-sensitive alleles of NSDHL cause CK syndrome.

CK syndrome (CKS) is an X-linked recessive intellectual disability syndrome characterized by dysmorphism, cortical brain malformations, and an asthenic build. Through an X chromosome single-nucleotide variant scan in the first reported family, we identified linkage to a 5 Mb region on Xq28. Sequencing of this region detected a segregating 3 bp deletion (c.696_698del [p.Lys232del]) in exon 7 of NAD(P) dependent steroid dehydrogenase-like (NSDHL), a gene that encodes an enzyme in the cholesterol biosynthesis pathway. We also found that males with intellectual disability in another reported family with an NSDHL mutation (c.1098 dup [p.Arg367SerfsX33]) have CKS. These two mutations, which alter protein folding, show temperature-sensitive protein stability and complementation in Erg26-deficient yeast. As described for the allelic disorder CHILD syndrome, cells and cerebrospinal fluid from CKS patients have increased methyl sterol levels. We hypothesize that methyl sterol accumulation, not only cholesterol deficiency, causes CKS, given that cerebrospinal fluid cholesterol, plasma cholesterol, and plasma 24S-hydroxycholesterol levels are normal in males with CKS. In summary, CKS expands the spectrum of cholesterol-related disorders and insight into the role of cholesterol in human development.

Acquired TNFRSF14 mutations in follicular lymphoma are associated with worse prognosis.

Clinical correlative studies have linked 1p36 deletions with worse prognosis in follicular lymphoma (FL). In this study, we sought to identify the critical gene(s) in this region that is responsible for conferring inferior prognosis. BAC array technology applied to 141 FL specimens detected a minimum region of deletion (MRD) of ∼97 kb within 1p36.32 in 20% of these cases. Frequent single-nucleotide polymorphism-detected copy-neutral loss of heterozygosity was also found in this region. Analysis of promoter CpGs in the MRD did not reveal differential patterns of DNA methylation in samples that differed in 1p36 status. Exon sequencing of MRD genes identified somatic alterations in the TNFRSF14 gene in 3 of 11 selected cases with matching normal DNA. An expanded cohort consisting of 251 specimens identified 46 cases (18.3%) with nonsynonymous mutations affecting TNFRSF14. Overall survival (OS) and disease-specific survival (DSS) were associated with the presence of TNFRSF14 mutation in patients whose overall treatment included rituximab. We further showed that inferior OS and DSS were most pronounced in patients whose lymphomas contained both TNFRSF14 mutations and 1p36 deletions after adjustment for the International Prognostic Index [hazard ratios of 3.65 (95% confidence interval, 1.35-9.878, P=0.011) and 3.19 (95% confidence interval, 1.06-9.57, P=0.039), respectively]. Our findings identify TNFRSF14 as a candidate gene associated with a subset of FL, based on frequent occurrence of acquired mutations and their correlation with inferior clinical outcomes.

Somatic mutations altering EZH2 (Tyr641) in follicular and diffuse large B-cell lymphomas of germinal-center origin.

Follicular lymphoma (FL) and the GCB subtype of diffuse large B-cell lymphoma (DLBCL) derive from germinal center B cells. Targeted resequencing studies have revealed mutations in various genes encoding proteins in the NF-kappaB pathway that contribute to the activated B-cell (ABC) DLBCL subtype, but thus far few GCB-specific mutations have been identified. Here we report recurrent somatic mutations affecting the polycomb-group oncogene EZH2, which encodes a histone methyltransferase responsible for trimethylating Lys27 of histone H3 (H3K27). After the recent discovery of mutations in KDM6A (UTX), which encodes the histone H3K27me3 demethylase UTX, in several cancer types, EZH2 is the second histone methyltransferase gene found to be mutated in cancer. These mutations, which result in the replacement of a single tyrosine in the SET domain of the EZH2 protein (Tyr641), occur in 21.7% of GCB DLBCLs and 7.2% of FLs and are absent from ABC DLBCLs. Our data are consistent with the notion that EZH2 proteins with mutant Tyr641 have reduced enzymatic activity in vitro.