An Eight-Week Trial Investigating the Efficacy and Tolerability of Atorvastatin for Children and Adolescents With Heterozygous Familial Hypercholesterolemia

This study aimed to assess the efficacy and tolerability of atorvastatin in Tanner stage (TS) 1 patients ages 6 to 10 years and TS ≥2 patients ages 10 to <18 years with genetically confirmed heterozygous familial hypercholesterolemia (HeFH) and a low density lipoprotein cholesterol (LDL-C) level of 4 mmol/l (155 mg/dl) or higher. In this open-label, 8-week study, 15 TS 1 children were treated initially with atorvastatin 5 mg/day and 24 TS ≥2 children with 10 mg/day. Doses were doubled at week 4 if the LDL-C target (<3.35 mmol/l [130 mg/dl]) was not achieved. The efficacy variables were the percentage change from baseline in LDL-C, total cholesterol (TC), triglycerides (TG), high density lipoprotein cholesterol (HDL-C), very low density lipoprotein cholesterol (VLDL-C), and apolipoprotein (Apo) A-I and Apo B. Safety evaluations included clinical monitoring, subject-reported adverse events (AEs), vital signs, and clinical laboratory tests. The mean values for LDL-C, TC, VLDL-C, and Apo B decreased by week 2 among all TS 1 and TS ≥2 patients, whereas TG, HDL-C, and Apo A-I varied considerably from week to week. After 8 weeks, the mean reduction in LDL-C was −40.7% ± 8.4 for the TS 1 children and −39.7% ± 10.3 for the TS ≥2 children. For the TS 1 patients, the mean reductions were −34.1% ± 6.9 for TC and −6.0% ± 32.1 for TG. The corresponding changes for the TS ≥2 patients were −35.6% ± 9.5 for TC and −21.1% ± 29.7 for TG. Four patients experienced mild to moderate treatment-related AEs. No serious AEs or discontinuations were reported. Overall, no difference in safety or tolerability was observed between the younger and older cohorts. Across the range of exposures after atorvastatin 5 to 10 mg (TS 1) or atorvastatin 10 to 20 mg (TS ≥2) doses for 8 weeks, clinically meaningful reductions in LDL-C, TC, VLDL-C, and Apo were observed with atorvastatin in pediatric patients who had HeFH. Atorvastatin also was well tolerated in this population

KELT-23Ab: A Hot Jupiter Transiting a Near-solar Twin Close to the TESS and JWST Continuous Viewing Zones

We announce the discovery of KELT-23Ab, a hot Jupiter transiting the relatively bright (V = 10.3) star BD+66 911 (TYC 4187-996-1), and characterize the system using follow-up photometry and spectroscopy. A global fit to the system yields host-star properties of K, , , , (cgs), and . KELT-23Ab is a hot Jupiter with a mass of , radius of , and density of g cm-3. Intense insolation flux from the star has likely caused KELT-23Ab to become inflated. The time of inferior conjunction is and the orbital period is days. There is strong evidence that KELT-23A is a member of a long-period binary star system with a less luminous companion, and due to tidal interactions, the planet is likely to spiral into its host within roughly a gigayear. This system has one of the highest positive ecliptic latitudes of all transiting planet hosts known to date, placing it near the Transiting Planet Survey Satellite and James Webb Space Telescope continuous viewing zones. Thus we expect it to be an excellent candidate for long-term monitoring and follow up with these facilities

Influenza Polymerase Activity Correlates with the Strength of Interaction between Nucleoprotein and PB2 through the Host-Specific Residue K/E627

The ribonucleoprotein (RNP) complex is the essential transcription-replication machinery of the influenza virus. It is composed of the trimeric polymerase (PA, PB1 and PB2), nucleoprotein (NP) and RNA. Elucidating the molecular mechanisms of RNP assembly is central to our understanding of the control of viral transcription and replication and the dependence of these processes on the host cell. In this report, we show, by RNP reconstitution assays and co-immunoprecipitation, that the interaction between NP and polymerase is crucial for the function of the RNP. The functional association of NP and polymerase involves the C-terminal ‘627’ domain of PB2 and it requires NP arginine-150 and either lysine-627 or arginine-630 of PB2. Using surface plasmon resonance, we demonstrate that the interaction between NP and PB2 takes place without the involvement of RNA. At 33, 37 and 41°C in mammalian cells, more positive charges at aa. 627 and 630 of PB2 lead to stronger NP-polymerase interaction, which directly correlates with the higher RNP activity. In conclusion, our study provides new information on the NP-PB2 interaction and shows that the strength of NP-polymerase interaction and the resulting RNP activity are promoted by the positive charges at aa. 627 and 630 of PB2

Sequencing of diverse mandarin, pummelo and orange genomes reveals complex history of admixture during citrus domestication

Cultivated citrus are selections from, or hybrids of, wild progenitor species whose identities and contributions to citrus domestication remain controversial. Here we sequence and compare citrus genomes-a high-quality reference haploid clementine genome and mandarin, pummelo, sweet-orange and sour-orange genomes-and show that cultivated types derive from two progenitor species. Although cultivated pummelos represent selections from one progenitor species, Citrus maxima, cultivated mandarins are introgressions of C. maxima into the ancestral mandarin species Citrus reticulata. The most widely cultivated citrus, sweet orange, is the offspring of previously admixed individuals, but sour orange is an F1 hybrid of pure C. maxima and C. reticulata parents, thus implying that wild mandarins were part of the early breeding germplasm. A Chinese wild 'mandarin' diverges substantially from C. reticulata, thus suggesting the possibility of other unrecognized wild citrus species. Understanding citrus phylogeny through genome analysis clarifies taxonomic relationships and facilitates sequence-directed genetic improvement

Mutations in Polymerase Genes Enhanced the Virulence of 2009 Pandemic H1N1 Influenza Virus in Mice

Influenza A virus can infect a wide variety of animal species with illness ranging from mild to severe, and is a continual cause for concern. Genetic mutations that occur either naturally or during viral adaptation in a poorly susceptible host are key mechanisms underlying the evolution and virulence of influenza A virus. Here, the variants containing PA-A36T or PB2-H357N observed in the mouse-adapted descendants of 2009 pandemic H1N1 virus (pH1N1), A/Sichuan/1/2009 (SC), were characterized. Both mutations enhanced polymerase activity in mammalian cells. These effects were confirmed using recombinant SC virus containing polymerase genes with wild type (WT) or mutant PA or PB2. The PA-A36T mutant showed enhanced growth property compared to the WT in both human A549 cells and porcine PK15 cells in vitro, without significant effect on viral propagation in murine LA-4 cells and pathogenicity in mice; however, it did enhance the lung virus titer. PB2-H357N variant demonstrated growth ability comparable to the WT in A549 cells, but replicated well in PK15, LA-4 cells and in mice with an enhanced pathogenic phenotype. Despite such mutations are rare in nature, they could be observed in avian H5 and H7 subtype viruses which were currently recognized to pose potential threat to human. Our findings indicated that pH1N1 may adapt well in mammals when acquiring these mutations. Therefore, future molecular epidemiological surveillance should include scrutiny of both markers because of their potential impact on pathogenesis

Sequencing of diverse mandarin, pummelo and orange genomes reveals complex history of admixture during citrus domestication

Cultivated citrus are selections from, or hybrids of, wild progenitor species whose identities and contributions to citrus domestication remain controversial. Here we sequence and compare citrus genomes-a high-quality reference haploid clementine genome and mandarin, pummelo, sweet-orange and sour-orange genomes-and show that cultivated types derive from two progenitor species. Although cultivated pummelos represent selections from one progenitor species, Citrus maxima, cultivated mandarins are introgressions of C. maxima into the ancestral mandarin species Citrus reticulata. The most widely cultivated citrus, sweet orange, is the offspring of previously admixed individuals, but sour orange is an F1 hybrid of pure C. maxima and C. reticulata parents, thus implying that wild mandarins were part of the early breeding germplasm. A Chinese wild 'mandarin' diverges substantially from C. reticulata, thus suggesting the possibility of other unrecognized wild citrus species. Understanding citrus phylogeny through genome analysis clarifies taxonomic relationships and facilitates sequence-directed genetic improvement. (Résumé d'auteur

Supporting work practices through telehealth: impact on nurses in peripheral regions

<p>Abstract</p> <p>Background</p> <p>In Canada, workforce shortages in the health care sector constrain the ability of the health care system to meet the needs of its population and of its health care professionals. This issue is of particular importance in peripheral regions of Quebec, where significant inequalities in workforce distribution between regions has lead to acute nursing shortages and increased workloads. Information and communication technologies (ICTs) are innovative solutions that can be used to develop strategies to optimise the use of available resources and to design new nursing work practices. However, current knowledge is still limited about the real impact of ICTs on nursing recruitment and retention. Our aim is to better understand how work practice reorganization, supported by ICTs, and particularly by telehealth, may influence professional, educational, and organizational factors relating to Quebec nurses, notably those working in peripheral regions.</p> <p>Methods/Design</p> <p>First, we will conduct a descriptive study on the issue of nursing recruitment. Stratified sampling will be used to select approximately twenty innovative projects relating to the reorganization of work practices based upon ICTs. Semi-structured interviews with key informants will determine professional, educational, and organizational recruitment factors. The results will be used to create a questionnaire which, using a convenience sampling method, will be mailed to 600 third year students and recent graduates of two Quebec university nursing faculties. Descriptive, correlation, and hierarchical regression analyses will be performed to identify factors influencing nursing graduates' intentions to practice in peripheral regions. Secondly, we will conduct five case studies pertaining to the issue of nursing retention. Five ICT projects in semi-urban, rural, and isolated regions have been identified. Qualitative data will be collected through field observation and approximately fifty semi-structured interviews with key stakeholders.</p> <p>Discussion</p> <p>Data from both parts of this research project will be jointly analysed using triangulation of researchers, theoretical approaches, methods, and results. Continuous exchanges with decision makers and periodic knowledge transfer activities are planned to facilitate the dissemination and utilization of research results in policies regarding the nursing recruitment and retention.</p

KELT-24b: A 5M_J Planet on a 5.6 day Well-Aligned Orbit around the Young V=8.3 F-star HD 93148

We present the discovery of KELT-24 b, a massive hot Jupiter orbiting a bright (V=8.3 mag, K=7.2 mag) young F-star with a period of 5.6 days. The host star, KELT-24 (HD 93148), has a T_(eff) =6508±49 K, a mass of M∗ = 1.461^(+0.056)_(−0.060) M_⊙, radius of R∗ = 1.506±0.022 R_⊙, and an age of 0.77^(+0.61)_(−0.42) Gyr. Its planetary companion (KELT-24 b) has a radius of R_P = 1.272^(+0.021)_(−0.022) R_J, a mass of MP = 5.18^(+0.21)_(−0.22) M_J, and from Doppler tomographic observations, we find that the planet's orbit is well-aligned to its host star's projected spin axis (λ = 2.6^(+5.1)_(−3.6)). The young age estimated for KELT-24 suggests that it only recently started to evolve from the zero-age main sequence. KELT-24 is the brightest star known to host a transiting giant planet with a period between 5 and 10 days. Although the circularization timescale is much longer than the age of the system, we do not detect a large eccentricity or significant misalignment that is expected from dynamical migration. The brightness of its host star and its moderate surface gravity make KELT-24b an intriguing target for detailed atmospheric characterization through spectroscopic emission measurements since it would bridge the current literature results that have primarily focused on lower mass hot Jupiters and a few brown dwarfs