A noninvasive multi-analyte diagnostic assay: Combining protein and DNA markers to stratify bladder cancer patients

Purpose: The authors recently reported the development of a noninvasive diagnostic assay using urinary matrix metalloproteinases (MMPs) as monitors of disease-free status and bladder cancer in high-risk populations. Using an approach called clinical intervention determining diagnostic (CIDD), they identified with high confidence those patients who could be excluded from additional intervention. To maximize performance, MMPs were combined with DNAbased markers and CIDD was applied to a population of patients undergoing monitoring for recurrence. Patients and methods: Urine samples were obtained from 323 patients, 48 of whom had a recurrence and 275 of whom did not have cancer upon cytoscopic evaluation. Twist1 and Nid2 methylation status was determined using methylation-specific polymerase chain reaction, FGFR3 mutational status by quantitative PCR, and MMP levels by enzyme-linked immunosorbent assay. Results: Using a combination of these DNA and protein markers, the authors identified with high confidence (97% negative predicted value) those patients who do not have cancer. Cutoffs were adjusted such that at 92% sensitivity, 51% of disease-free patients might be triaged from receiving further tests. Conclusion: The multi-analyte diagnostic readout assay described here is the first to combine protein and DNA biomarkers into one assay for optimal clinical performance. Using this approach, the detection of FGFR3 mutations and Twist1 and Nid2 methylation in the urine of patients undergoing bladder cancer recurrence screening increase the sensitivity and negative predictive value at an established MMP protein cutoff. This noninvasive urinary diagnostic assay could lead to the more efficient triage of patients undergoing recurrence monitoring

Global Genomic Analysis of Intraductal Papillary Mucinous Neoplasms of the Pancreas Reveals Significant Molecular Differences Compared to Ductal Adenocarcinoma

Objective: To determine whether intraductal papillary mucinous neoplasms of the pancreas (IPMNs) have a different genetic background compared with ductal adenocarcinoma (PDAC). Summary Background Data: The biologic and clinical behavior of IPMNs and IPMN-associated adenocarcinomas is different from PDAC in having a less aggressive tumor growth and significantly improved survival. Up to date, the molecular mechanisms underlying the clinical behavior of IPMNs are incompletely understood. Methods: 128 cystic pancreatic lesions were prospectively identified during the course of 2 years. From the corresponding surgical specimens, 57 IPMNs were separated and subdivided by histologic criteria into those with low-grade dysplasia, moderate dysplasia, high-grade dysplasia, and invasive cancer. Twenty specimens were suitable for DNA isolation and subsequent performance of array CGH. Results: While none of the IPMNs with low-grade dysplasia displayed detectable chromosomal aberrations, IPMNs with moderate and high-grade dysplasia showed frequent copy number alterations. Commonly lost regions were located on chromosome 5q, 6q, 10q, 11q, 13q, 18q, and 22q. The incidence of loss of chromosome 5q, 6q, and 11q was significantly higher in IPMNs with high-grade dysplasia or invasion compared with PDAC. Ten of 13 IPMNs with moderate dysplasia or malignancy had loss of part or all of chromosome 6q, with a minimal deleted region between linear positions 78.0 and 130.0. Conclusions: This study is the first to use array CGH to characterize IPMNs. Recurrent cytogenetic alterations were identified and were different than those described in PDAC. Array CGH may help distinguish between these 2 entities and give insight into the differences in their biology and prognosis

Forecasting substantial data revisions in the presence of model uncertainty

A recent revision to the preliminary measurement of GDP(E) growth for 2003Q2 caused considerable press attention, provoked a public enquiry and prompted a number of reforms to UK statistical reporting procedures. In this article, we compute the probability of 'substantial revisions' that are greater (in absolute value) than the controversial 2003 revision. The predictive densities are derived from Bayesian model averaging over a wide set of forecasting models including linear, structural break and regime-switching models with and without heteroscedasticity. Ignoring the nonlinearities and model uncertainty yields misleading predictives and obscures recent improvements in the quality of preliminary UK macroeconomic measurements

Treatment of Psoriasis in Patients With Psoriatic Arthritis: An Updated Literature Review Informing the 2021 GRAPPA Treatment Recommendations

Objective. Our aim was to summarize and evaluate the current quality of evidence regarding the efficacy of therapies for cutaneous psoriasis (PsO) in patients with psoriatic arthritis (PsA).Methods. A literature search of MEDLINE, Embase, Cochrane Library databases, and conference abstracts was conducted to identify interventional randomized controlled trials in patients with PsA between February 2013 and December 2021. Studies were included if PsO outcomes included achieving at least 75% improvement in the Psoriasis Area and Severity Index and the blinded comparison period was >= 10 weeks. The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology was employed to assess quality of the evidence to inform and update the 2021 Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) treatment recommendations.Results. A total of 116 studies and 36 abstracts identified in the initial search were screened. A total of 37 studies (40 treatment arms) met the criteria for final inclusion. Phosphodiesterase 4 inhibitors, Janus kinase inhibitors, and tyrosine kinase 2 inhibitors, interleukin 17 inhibitors (IL-17i), IL-12/23i, IL-23i, and tumor necrosis factor inhibitors (TNFi) had high-quality data broadly supporting the efficacy of each class for plaque PsO over placebo. Head-to-head studies with high-quality data supported both IL-17i and IL-23i over TNFi.Conclusion. Several pharmacologic therapeutic classes have high-quality evidence demonstrating efficacy for cutaneous PsO in the PsA population. The findings will be integrated into the 2021 GRAPPA treatment recommendations, intended to guide selection of a therapeutic class where efficacy in 1 or more cutaneous or musculoskeletal domains is required

Entomological risk assessment for dengue virus transmission during 2016-2020 in Kamphaeng Phet, Thailand

Individual houses with high risks of dengue virus (DENV) transmission might be a source of virus transmission within the neighborhood. We conducted an entomological risk assessment for DENV transmission at the household level, comprising family cohort members residing in the same location, to assess the risk for dengue virus transmitted by mosquito vectors. The studies were conducted in Kamphaeng Phet Province, Thailand, during 2016–2020. Entomological investigations were performed in 35 cohort families on day 1 and day 14 after receiving dengue case reports. DENV was found in 22 Aedes samples (4.9%) out of 451 tested samples. A significantly higher DENV infection rate was detected in vectors collected on day 1 (6.64%) compared to those collected on day 14 (1.82%). Annual vector surveillance was carried out in 732 houses, with 1002 traps catching 3653 Aedes females. The majority of the 13,228 water containers examined were made from plastic and clay, with used tires serving as a primary container, with 59.55% larval abundance. Larval indices, as indicators of dengue epidemics and to evaluate disease and vector control approaches, were calculated. As a result, high values of larval indices indicated the considerably high risk of dengue transmission in these communities

Rapamycin-mediated mouse lifespan extension: Late-life dosage regimes with sex-specific effects.

To see if variations in timing of rapamycin (Rapa), administered to middle aged mice starting at 20 months, would lead to different survival outcomes, we compared three dosing regimens. Initiation of Rapa at 42 ppm increased survival significantly in both male and female mice. Exposure to Rapa for a 3-month period led to significant longevity benefit in males only. Protocols in which each month of Rapa treatment was followed by a month without Rapa exposure were also effective in both sexes, though this approach was less effective than continuous exposure in female mice. Interpretation of these results is made more complicated by unanticipated variation in patterns of weight gain, prior to the initiation of the Rapa treatment, presumably due to the use of drug-free food from two different suppliers. The experimental design included tests of four other drugs, minocycline, β-guanidinopropionic acid, MitoQ, and 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG), but none of these led to a change in survival in either sex

A detailed clinical and molecular survey of subjects with nonsyndromic USH2A retinopathy reveals an allelic hierarchy of disease-causing variants.

Defects in USH2A cause both isolated retinal disease and Usher syndrome (ie, retinal disease and deafness). To gain insights into isolated/nonsyndromic USH2A retinopathy, we screened USH2A in 186 probands with recessive retinal disease and no hearing complaint in childhood (discovery cohort) and in 84 probands with recessive retinal disease (replication cohort). Detailed phenotyping, including retinal imaging and audiological assessment, was performed in individuals with two likely disease-causing USH2A variants. Further genetic testing, including screening for a deep-intronic disease-causing variant and large deletions/duplications, was performed in those with one likely disease-causing change. Overall, 23 of 186 probands (discovery cohort) were found to harbour two likely disease-causing variants in USH2A. Some of these variants were predominantly associated with nonsyndromic retinal degeneration ('retinal disease-specific'); these included the common c.2276 G>T, p.(Cys759Phe) mutation and five additional variants: c.2802 T>G, p.(Cys934Trp); c.10073 G>A, p.(Cys3358Tyr); c.11156 G>A, p.(Arg3719His); c.12295-3 T>A; and c.12575 G>A, p.(Arg4192His). An allelic hierarchy was observed in the discovery cohort and confirmed in the replication cohort. In nonsyndromic USH2A disease, retinopathy was consistent with retinitis pigmentosa and the audiological phenotype was variable. USH2A retinopathy is a common cause of nonsyndromic recessive retinal degeneration and has a different mutational spectrum to that observed in Usher syndrome. The following model is proposed: the presence of at least one 'retinal disease-specific' USH2A allele in a patient with USH2A-related disease results in the preservation of normal hearing. Careful genotype-phenotype studies such as this will become increasingly important, especially now that high-throughput sequencing is widely used in the clinical setting.European Journal of Human Genetics advance online publication, 4 February 2015; doi:10.1038/ejhg.2014.283

Rapamycin-mediated mouse lifespan extension: Late-life dosage regimes with sex-specific effects.

To see if variations in timing of rapamycin (Rapa), administered to middle aged mice starting at 20 months, would lead to different survival outcomes, we compared three dosing regimens. Initiation of Rapa at 42 ppm increased survival significantly in both male and female mice. Exposure to Rapa for a 3-month period led to significant longevity benefit in males only. Protocols in which each month of Rapa treatment was followed by a month without Rapa exposure were also effective in both sexes, though this approach was less effective than continuous exposure in female mice. Interpretation of these results is made more complicated by unanticipated variation in patterns of weight gain, prior to the initiation of the Rapa treatment, presumably due to the use of drug-free food from two different suppliers. The experimental design included tests of four other drugs, minocycline, β-guanidinopropionic acid, MitoQ, and 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG), but none of these led to a change in survival in either sex

Real-Time and Post-Processed Orbit Determination and Positioning

Novel methods and systems for the accurate and efficient processing of real-time and latent global navigation satellite systems (GNSS) data are described. Such methods and systems can perform orbit determination of GNSS satellites, orbit determination of satellites carrying GNSS receivers, positioning of GNSS receivers, and environmental monitoring with GNSS data

Search for Event Rate Modulation in XENON100 Electronic Recoil Data

We have searched for periodic variations of the electronic recoil event rate in the (2-6) keV energy range recorded between February 2011 and March 2012 with the XENON100 detector, adding up to 224.6 live days in total. Following a detailed study to establish the stability of the detector and its background contributions during this run, we performed an un-binned profile likelihood analysis to identify any periodicity up to 500 days. We find a global significance of less than 1 sigma for all periods suggesting no statistically significant modulation in the data. While the local significance for an annual modulation is 2.8 sigma, the analysis of a multiple-scatter control sample and the phase of the modulation disfavor a dark matter interpretation. The DAMA/LIBRA annual modulation interpreted as a dark matter signature with axial-vector coupling of WIMPs to electrons is excluded at 4.8 sigma.Comment: 6 pages, 4 figure