Intermittent preventive treatment with dihydroartemisinin-piperaquine in Ugandan schoolchildren selects for Plasmodium falciparum transporter polymorphisms that modify drug sensitivity.

Dihydroartemisinin-piperaquine (DP) offers prolonged protection against malaria, but its impact on Plasmodium falciparum drug sensitivity is uncertain. In a trial of intermittent preventive treatment in schoolchildren in Tororo, Uganda, in 2011 to 2012, monthly DP for 1 year decreased the incidence of malaria by 96% compared to placebo; DP once per school term offered protection primarily during the first month after therapy. To assess the impact of DP on selection of drug resistance, we compared the prevalence of key polymorphisms in isolates that emerged at different intervals after treatment with DP. Blood obtained monthly and at each episode of fever was assessed for P. falciparum parasitemia by microscopy. Samples from 160 symptomatic and 650 asymptomatic episodes of parasitemia were assessed at 4 loci (N86Y, Y184F, and D1246Y in pfmdr1 and K76T in pfcrt) that modulate sensitivity to aminoquinoline antimalarials, utilizing a ligase detection reaction-fluorescent microsphere assay. For pfmdr1 N86Y and pfcrt K76T, but not the other studied polymorphisms, the prevalences of mutant genotypes were significantly greater in children who had received DP within the past 30 days than in those not treated within 60 days (86Y, 18.0% versus 8.3% [P = 0.03]; 76T, 96.0% versus 86.1% [P = 0.05]), suggesting selective pressure of DP. Full sequencing of pfcrt in a subset of samples did not identify additional polymorphisms selected by DP. In summary, parasites that emerged soon after treatment with DP were more likely than parasites not under drug pressure to harbor pfmdr1 and pfcrt polymorphisms associated with decreased sensitivity to aminoquinoline antimalarials. (This study has been registered at ClinicalTrials.gov under no. NCT01231880.)

Law Libraries and Laboratories: The Legacies of Langdell and His Metaphor

Law Librarians and others have often referred to Harvard Law School Dean C.C. Langdell’s statements that the law library is the lawyer’s laboratory. Professor Danner examines the context of what Langdell through his other writings, the educational environment at Harvard in the late nineteenth century, and the changing perceptions of university libraries generally. He then considers how the “laboratory metaphor” has been applied by librarians and legal scholars during the twentieth century and into the twenty-first. The article closes with thoughts on Langdell’s legacy for law librarians and the usefulness of the laboratory metaphor

SLUDGE TREATMENT PROJECT PHASE 1 SLUDGE STORAGE OPTIONS ASSESSMENT OF T PLANT VERSUS ALTERNATE STORAGE FACILITY

The CH2M HILL Plateau Remediation Company (CHPRC) has recommended to the U.S. Department of Energy (DOE) a two phase approach for removal and storage (Phase 1) and treatment and packaging for offsite shipment (Phase 2) of the sludge currently stored within the 105-K West Basin. This two phased strategy enables early removal of sludge from the 105-K West Basin by 2015, allowing remediation of historical unplanned releases of waste and closure of the 100-K Area. In Phase 1, the sludge currently stored in the Engineered Containers and Settler Tanks within the 105-K West Basin will be transferred into sludge transport and storage containers (STSCs). The STSCs will be transported to an interim storage facility. In Phase 2, sludge will be processed (treated) to meet shipping and disposal requirements and the sludge will be packaged for final disposal at a geologic repository. The purpose of this study is to evaluate two alternatives for interim Phase 1 storage of K Basin sludge. The cost, schedule, and risks for sludge storage at a newly-constructed Alternate Storage Facility (ASF) are compared to those at T Plant, which has been used previously for sludge storage. Based on the results of the assessment, T Plant is recommended for Phase 1 interim storage of sludge. Key elements that support this recommendation are the following: (1) T Plant has a proven process for storing sludge; (2) T Plant storage can be implemented at a lower incremental cost than the ASF; and (3) T Plant storage has a more favorable schedule profile, which provides more float, than the ASF. Underpinning the recommendation of T Plant for sludge storage is the assumption that T Plant has a durable, extended mission independent of the K Basin sludge interim storage mission. If this assumption cannot be validated and the operating costs of T Plant are borne by the Sludge Treatment Project, the conclusions and recommendations of this study would change. The following decision-making strategy, which is dependent on the confidence that DOE has in the long term mission for T Plant, is proposed: (1) If the confidence level in a durable, extended T Plant mission independent of sludge storage is high, then the Sludge Treatment Project (STP) would continue to implement the path forward previously described in the Alternatives Report (HNF-39744). Risks to the sludge project can be minimized through the establishment of an Interface Control Document (ICD) defining agreed upon responsibilities for both the STP and T Plant Operations regarding the transfer and storage of sludge and ensuring that the T Plant upgrade and operational schedule is well integrated with the sludge storage activities. (2) If the confidence level in a durable, extended T Plant mission independent of sludge storage is uncertain, then the ASF conceptual design should be pursued on a parallel path with preparation of T Plant for sludge storage until those uncertainties are resolved. (3) Finally, if the confidence level in a durable, extended T Plant mission independent of sludge storage is low, then the ASF design should be selected to provide independence from the T Plant mission risk

Changing antimalarial drug resistance patterns identified by surveillance at three sites in Uganda.

: We assessed Plasmodium falciparum drug resistance markers in parasites collected in 2012, 2013, and 2015 at 3 sites in Uganda. The prevalence and frequency of parasites with mutations in putative transporters previously associated with resistance to aminoquinolines, but increased sensitivity to lumefantrine (pfcrt 76T; pfmdr1 86Y and 1246Y), decreased markedly at all sites. Antifolate resistance mutations were common, with apparent emergence of mutations (pfdhfr 164L; pfdhps 581G) associated with high-level resistance. K13 mutations linked to artemisinin resistance were uncommon and did not increase over time. Changing malaria treatment practices have been accompanied by profound changes in markers of resistance.<br/

Choice of activity-intensity classification thresholds impacts upon accelerometer-assessed physical activity-health relationships in children

It is unknown whether using different published thresholds (PTs) for classifying physical activity (PA) impacts upon activity-health relationships. This study explored whether relationships between PA (sedentary [SED], light PA [LPA], moderate PA [MPA], moderate-to-vigorous PA, vigorous PA [VPA]) and health markers differed in children when classified using three different PTs

Low levels of amyloid-beta and its transporters in neonatal rats with and without hydrocephalus

<p>Abstract</p> <p>Background</p> <p>Previous studies in aging animals have shown that amyloid-beta protein (Aβ) accumulates and its transporters, low-density lipoprotein receptor-related protein-1 (LRP-1) and the receptor for advanced glycation end products (RAGE) are impaired during hydrocephalus. Furthermore, correlations between astrocytes and Aβ have been found in human cases of normal pressure hydrocephalus (NPH) and Alzheimer's disease (AD). Because hydrocephalus occurs frequently in children, we evaluated the expression of Aβ and its transporters and reactive astrocytosis in animals with neonatal hydrocephalus.</p> <p>Methods</p> <p>Hydrocephalus was induced in neonatal rats by intracisternal kaolin injections on post-natal day one, and severe ventriculomegaly developed over a three week period. MRI was performed on post-kaolin days 10 and 21 to document ventriculomegaly. Animals were sacrificed on post-kaolin day 21. For an age-related comparison, tissue was used from previous studies when hydrocephalus was induced in a group of adult animals at either 6 months or 12 months of age. Tissue was processed for immunohistochemistry to visualize LRP-1, RAGE, Aβ, and glial fibrillary acidic protein (GFAP) and with quantitative real time reverse transcriptase polymerase chain reaction (qRT-PCR) to quantify expression of LRP-1, RAGE, and GFAP.</p> <p>Results</p> <p>When 21-day post-kaolin neonatal hydrocephalic animals were compared to adult (6–12 month old) hydrocephalic animals, immunohistochemistry demonstrated levels of Aβ, RAGE, and LRP-1 that were substantially lower in the younger animals; in contrast, GFAP levels were elevated in both young and old hydrocephalic animals. When the neonatal hydrocephalic animals were compared to age-matched controls, qRT-PCR demonstrated no significant changes in Aβ, LRP-1 and RAGE. However, immunohistochemistry showed very small increases or decreases in individual proteins. Furthermore, qRT-PCR indicated statistically significant increases in GFAP.</p> <p>Conclusion</p> <p>Neonatal rats with and without hydrocephalus had low expression of Aβ and its transporters when compared to adult rats with hydrocephalus. No statistical differences were observed in Aβ and its transporters between the control and hydrocephalic neonatal animals.</p

Asymptotic behaviour and optimal word size for exact and approximate word matches between random sequences

BACKGROUND: The number of k-words shared between two sequences is a simple and effcient alignment-free sequence comparison method. This statistic, D(2), has been used for the clustering of EST sequences. Sequence comparison based on D(2 )is extremely fast, its runtime is proportional to the size of the sequences under scrutiny, whereas alignment-based comparisons have a worst-case run time proportional to the square of the size. Recent studies have tackled the rigorous study of the statistical distribution of D(2), and asymptotic regimes have been derived. The distribution of approximate k-word matches has also been studied. RESULTS: We have computed the D(2 )optimal word size for various sequence lengths, and for both perfect and approximate word matches. Kolmogorov-Smirnov tests show D(2 )to have a compound Poisson distribution at the optimal word size for small sequence lengths (below 400 letters) and a normal distribution at the optimal word size for large sequence lengths (above 1600 letters). We find that the D(2 )statistic outperforms BLAST in the comparison of artificially evolved sequences, and performs similarly to other methods based on exact word matches. These results obtained with randomly generated sequences are also valid for sequences derived from human genomic DNA. CONCLUSION: We have characterized the distribution of the D(2 )statistic at optimal word sizes. We find that the best trade-off between computational efficiency and accuracy is obtained with exact word matches. Given that our numerical tests have not included sequence shuffling, transposition or splicing, the improvements over existing methods reported here underestimate that expected in real sequences. Because of the linear run time and of the known normal asymptotic behavior, D(2)-based methods are most appropriate for large genomic sequences

Influence of family and friend smoking on intentions to smoke and smoking-related attitudes and refusal self-efficacy among 9-10 year old children from deprived neighbourhoods: a cross-sectional study.

BACKGROUND: Smoking often starts in early adolescence and addiction can occur rapidly. For effective smoking prevention there is a need to identify at risk groups of preadolescent children and whether gender-specific intervention components are necessary. This study aimed to examine associations between mother, father, sibling and friend smoking and cognitive vulnerability to smoking among preadolescent children living in deprived neighbourhoods. METHODS: Cross-sectional data was collected from 9-10 year old children (n =1143; 50.7% girls; 85.6% White British) from 43 primary schools in Merseyside, England. Children completed a questionnaire that assessed their smoking-related behaviour, intentions, attitudes, and refusal self-efficacy, as well as parent, sibling and friend smoking. Data for boys and girls were analysed separately using multilevel linear and logistic regression models, adjusting for individual cognitions and school and deprivation level. RESULTS: Compared to girls, boys had lower non-smoking intentions (P = 0.02), refusal self-efficacy (P = 0.04) and were less likely to agree that smoking is 'definitely' bad for health (P < 0.01). Friend smoking was negatively associated with non-smoking intentions in girls (P < 0.01) and boys (P < 0.01), and with refusal self-efficacy in girls (P < 0.01). Sibling smoking was negatively associated with non-smoking intentions in girls (P < 0.01) but a positive association was found in boys (P = 0.02). Boys who had a smoking friend were less likely to 'definitely' believe that the smoke from other people's cigarettes is harmful (OR 0.57, 95% CI: 0.35 to 0.91, P = 0.02). Further, boys with a smoking friend (OR 0.38, 95% CI: 0.21 to 0.69, P < 0.01) or a smoking sibling (OR 0.45, 95% CI: 0.21 to 0.98) were less likely to 'definitely' believe that smoking is bad for health. CONCLUSION: This study indicates that sibling and friend smoking may represent important influences on 9-10 year old children's cognitive vulnerability toward smoking. Whilst some differential findings by gender were observed, these may not be sufficient to warrant separate prevention interventions. However, further research is needed

Lambda and Antilambda polarization from deep inelastic muon scattering

We report results of the first measurements of Lambda and Antilambda polarization produced in deep inelastic polarized muon scattering on the nucleon. The results are consistent with an expected trend towards positive polarization with increasing x_F. The polarizations of Lambda and Antilambda appear to have opposite signs. A large negative polarization for Lambda at low positive x_F is observed and is not explained by existing models.A possible interpretation is presented.Comment: 9 pages, 2 figure

Kaposi's Sarcoma-Associated Herpesvirus ORF57 Protein Binds and Protects a Nuclear Noncoding RNA from Cellular RNA Decay Pathways

The control of RNA stability is a key determinant in cellular gene expression. The stability of any transcript is modulated through the activity of cis- or trans-acting regulatory factors as well as cellular quality control systems that ensure the integrity of a transcript. As a result, invading viral pathogens must be able to subvert cellular RNA decay pathways capable of destroying viral transcripts. Here we report that the Kaposi's sarcoma-associated herpesvirus (KSHV) ORF57 protein binds to a unique KSHV polyadenylated nuclear RNA, called PAN RNA, and protects it from degradation by cellular factors. ORF57 increases PAN RNA levels and its effects are greatest on unstable alleles of PAN RNA. Kinetic analysis of transcription pulse assays shows that ORF57 protects PAN RNA from a rapid cellular RNA decay process, but ORF57 has little effect on transcription or PAN RNA localization based on chromatin immunoprecipitation and in situ hybridization experiments, respectively. Using a UV cross-linking technique, we further demonstrate that ORF57 binds PAN RNA directly in living cells and we show that binding correlates with function. In addition, we define an ORF57-responsive element (ORE) that is necessary for ORF57 binding to PAN RNA and sufficient to confer ORF57-response to a heterologous intronless β-globin mRNA, but not its spliced counterparts. We conclude that ORF57 binds to viral transcripts in the nucleus and protects them from a cellular RNA decay pathway. We propose that KSHV ORF57 protein functions to enhance the nuclear stability of intronless viral transcripts by protecting them from a cellular RNA quality control pathway