Significant improvements in self-reported gastrointestinal tolerability, quality of life, patient satisfaction, and adherence with lopinavir/ritonavir tablet formulation compared with soft gel capsules

<p>Abstract</p> <p>Background</p> <p>The tablet formulation of ritonavir-boosted lopinavir (LPV/r; Kaletra^®) has many advantages over the soft gel capsule (SGC) formulation, including lower pill count, no refrigeration requirement, and no dietary restrictions. These advantages may help improve patient compliance and therefore increase adherence to treatment. However, there are limited data regarding patient preferences and only recently was the comparative efficacy and tolerability data of LPV/r SGC versus tablet formulation presented at an international conference. To address this deficit, we conducted a market research survey to assess potential tolerability benefits, patient satisfaction, changes in adherence, and formulation preference in patients switching from SGCs to the tablet formulation. Data from 332 patients who switched from LPV/r SGCs twice-daily (BID) to tablets BID and 41 patients who switched from LPV/r SGCs BID or once daily (QD) to tablets QD were analyzed.</p> <p>Results</p> <p>Switching from SGCs to a tablet formulation of LPV/r was associated with increased patient satisfaction, tolerability and self-reported adherence to treatment; gastrointestinal side effects were reduced. In addition, respondents indicated that they preferred the tablet formulation to the SGC.</p> <p>Conclusion</p> <p>The LPV/r tablet formulation provides HIV-infected patients with multiple benefits over the SGC in terms of tolerability and convenience. Additional assessments to further define the tolerability profile of the LPV/r tablet, including studies using once-daily dosing, are warranted.</p

A statistical approach to finding overlooked genetic associations

<p>Abstract</p> <p>Background</p> <p>Complexity and noise in expression quantitative trait loci (eQTL) studies make it difficult to distinguish potential regulatory relationships among the many interactions. The predominant method of identifying eQTLs finds associations that are significant at a genome-wide level. The vast number of statistical tests carried out on these data make false negatives very likely. Corrections for multiple testing error render genome-wide eQTL techniques unable to detect modest regulatory effects.</p> <p>We propose an alternative method to identify eQTLs that builds on traditional approaches. In contrast to genome-wide techniques, our method determines the significance of an association between an expression trait and a locus with respect to the set of all associations to the expression trait. The use of this specific information facilitates identification of expression traits that have an expression profile that is characterized by a single exceptional association to a locus.</p> <p>Our approach identifies expression traits that have exceptional associations regardless of the genome-wide significance of those associations. This property facilitates the identification of possible false negatives for genome-wide significance. Further, our approach has the property of prioritizing expression traits that are affected by few strong associations. Expression traits identified by this method may warrant additional study because their expression level may be affected by targeting genes near a single locus.</p> <p>Results</p> <p>We demonstrate our method by identifying eQTL hotspots in <it>Plasmodium falciparum </it>(malaria) and <it>Saccharomyces cerevisiae </it>(yeast). We demonstrate the prioritization of traits with few strong genetic effects through Gene Ontology (GO) analysis of Yeast. Our results are strongly consistent with results gathered using genome-wide methods and identify additional hotspots and eQTLs.</p> <p>Conclusions</p> <p>New eQTLs and hotspots found with this method may represent regions of the genome or biological processes that are controlled through few relatively strong genetic interactions. These points of interest warrant experimental investigation.</p

Transient perceptual neglect: visual working memory load affects conscious object processing

Visual working memory (VWM) is a capacity-limited cognitive resource that plays an important role in complex cognitive behaviors. Recent studies indicate that regions subserving VWM may play a role in the perception and recognition of visual objects, suggesting that conscious object perception may depend on the same cognitive and neural architecture that supports the maintenance of visual object information. In the present study, we examined this question by testing object processing under a concurrent VWM load. Under a high VWM load, recognition was impaired for objects presented in the left visual field, in particular when two objects were presented simultaneously. Multivariate fMRI revealed that two independent but partially overlapping networks of brain regions contribute to object recognition. The first network consisted of regions involved in VWM encoding and maintenance. Importantly, these regions were also sensitive to object load. The second network comprised regions of the ventral temporal lobes traditionally associated with object recognition. Importantly, activation in both networks predicted object recognition performance. These results indicate that information processing in regions that mediate VWM may be critical to conscious visual perception. Moreover, the observation of a hemifield asymmetry in object recognition performance has important theoretical and clinical significance for the study of visual neglect

High-throughput cis-regulatory element discovery in the vector mosquito Aedes aegypti

BACKGROUND: Despite substantial progress in mosquito genomic and genetic research, few cis-regulatory elements (CREs), DNA sequences that control gene expression, have been identified in mosquitoes or other non-model insects. Formaldehyde-assisted isolation of regulatory elements paired with DNA sequencing, FAIRE-seq, is emerging as a powerful new high-throughput tool for global CRE discovery. FAIRE results in the preferential recovery of open chromatin DNA fragments that are not bound by nucleosomes, an evolutionarily conserved indicator of regulatory activity, which are then sequenced. Despite the power of the approach, FAIRE-seq has not yet been applied to the study of non-model insects. In this investigation, we utilized FAIRE-seq to profile open chromatin and identify likely regulatory elements throughout the genome of the human disease vector mosquito Aedes aegypti. We then assessed genetic variation in the regulatory elements of dengue virus susceptible (Moyo-S) and refractory (Moyo-R) mosquito strains. RESULTS: Analysis of sequence data obtained through next generation sequencing of FAIRE DNA isolated from A. aegypti embryos revealed >121,000 FAIRE peaks (FPs), many of which clustered in the 1 kb 5' upstream flanking regions of genes known to be expressed at this stage. As expected, known transcription factor consensus binding sites were enriched in the FPs, and of these FoxA1, Hunchback, Gfi, Klf4, MYB/ph3 and Sox9 are most predominant. All of the elements tested in vivo were confirmed to drive gene expression in transgenic Drosophila reporter assays. Of the >13,000 single nucleotide polymorphisms (SNPs) recently identified in dengue virus-susceptible and refractory mosquito strains, 3365 were found to map to FPs. CONCLUSION: FAIRE-seq analysis of open chromatin in A. aegypti permitted genome-wide discovery of CREs. The results of this investigation indicate that FAIRE-seq is a powerful tool for identification of regulatory DNA in the genomes of non-model organisms, including human disease vector mosquitoes

In-One-Continuity Rectal Excision and Anal Mucosectomy of a Giant Villous Adenoma: An Alternative Surgical Approach

Background: The authors present a woman suffering from McKittrick-Wheelock syndrome (MKWS) with a giant rectal villous adenoma. MKWS is a rare disorder caused by fluid and electrolyte hypersecretion from a rectal tumor. The most frequently reported tumors are villous adenomas. Symptoms of dehydration with severe hyponatremia, hypokalemia, metabolic acidosis and acute renal failure are typical in MKWS. Several options for operation have been reported, such as a transsacral approach (according to Kraske), transanal endoscopic microsurgery (TEM) or total mesorectal excision (TME). In this case we report an alternative surgical approach: in-one-continuity transanal mucosectomy and transabdominal TME with a handsewn colonic-anal anastomosis. Case: A 54-year-old woman had a history of hospital admissions because of repeated bouts of dehydration with electrolyte disorders since 2004. At admission she presented with prerenal azotemia, hyponatremia and severe hypokalemia in combination with watery stools. At colonoscopy an 8-cm villous adenoma was seen in the rectum. Dehydration and electrolyte disturbances were treated by appropriate intravenous fluid administration. An in-one-continuity anal mucosectomy and complete rectal excision were performed and restored by a handmade colonic-anal anastomosis. Postoperative recovery was uneventful. Conclusion: MKWS can be a difficult problem to assess in both gastroenterological and nephrological ways. Patients may develop severe complications which require surgical intervention in some cases. In-one-continuity transanal mucosectomy and rectum excision with a handmade colonic-anal anastomosis seemed to be a new and solid surgical therapeutic option in this case

The SKA Particle Array Prototype: The First Particle Detector at the Murchison Radio-astronomy Observatory

We report on the design, deployment, and first results from a scintillation detector deployed at the Murchison Radio-astronomy Observatory (MRO). The detector is a prototype for a larger array -- the Square Kilometre Array Particle Array (SKAPA) -- planned to allow the radio-detection of cosmic rays with the Murchison Widefield Array and the low-frequency component of the Square Kilometre Array. The prototype design has been driven by stringent limits on radio emissions at the MRO, and to ensure survivability in a desert environment. Using data taken from Nov.\ 2018 to Feb.\ 2019, we characterize the detector response while accounting for the effects of temperature fluctuations, and calibrate the sensitivity of the prototype detector to through-going muons. This verifies the feasibility of cosmic ray detection at the MRO. We then estimate the required parameters of a planned array of eight such detectors to be used to trigger radio observations by the Murchison Widefield Array.Comment: 17 pages, 14 figures, 3 table

Nuclear Cryogenic Propulsion Stage

The fundamental capability of Nuclear Thermal Propulsion (NTP) is game changing for space exploration. A first generation Nuclear Cryogenic Propulsion Stage (NCPS) based on NTP could provide high thrust at a specific impulse above 900 s, roughly double that of state of the art chemical engines. Characteristics of fission and NTP indicate that useful first generation systems will provide a foundation for future systems with extremely high performance. The role of the NCPS in the development of advanced nuclear propulsion systems could be analogous to the role of the DC-3 in the development of advanced aviation. Progress made under the NCPS project could help enable both advanced NTP and advanced NEP

Assembly of the algal CO2-fixing organelle, the pyrenoid, is guided by a Rubisco-binding motif

Approximately one-third of the Earth's photosynthetic CO2 assimilation occurs in a pyrenoid, an organelle containing the CO2-fixing enzyme Rubisco. How constituent proteins are recruited to the pyrenoid and how the organelle's subcompartments-membrane tubules, a surrounding phase-separated Rubisco matrix, and a peripheral starch sheath-are held together is unknown. Using the model alga Chlamydomonas reinhardtii, we found that pyrenoid proteins share a sequence motif. We show that the motif is necessary and sufficient to target proteins to the pyrenoid and that the motif binds to Rubisco, suggesting a mechanism for targeting. The presence of the Rubisco-binding motif on proteins that localize to the tubules and on proteins that localize to the matrix-starch sheath interface suggests that the motif holds the pyrenoid's three subcompartments together. Our findings advance our understanding of pyrenoid biogenesis and illustrate how a single protein motif can underlie the architecture of a complex multilayered phase-separated organelle