Strain 68-1 rhesus cytomegalovirus (RhCMV) vectors expressing simian immunodeficiency virus (SIV) antigens elicit CD8
T cells recognizing epitopes presented by major histocompatibility complex II ...(MHC-II) and MHC-E but not MHC-Ia. These immune responses mediate replication arrest of SIV in 50 to 60% of monkeys. We show that the peptide VMAPRTLLL (VL9) embedded within the RhCMV protein Rh67 promotes intracellular MHC-E transport and recognition of RhCMV-infected fibroblasts by MHC-E-restricted CD8
T cells. Deletion or mutation of viral VL9 abrogated MHC-E-restricted CD8
T cell priming, resulting in CD8
T cell responses exclusively targeting MHC-II-restricted epitopes. These responses were comparable in magnitude and differentiation to responses elicited by 68-1 vectors but did not protect against SIV. Thus, Rh67-enabled direct priming of MHC-E-restricted T cells is crucial for RhCMV/SIV vaccine efficacy.
Abstract
High-quality, representative serological surveys allow direct estimates of immunity profiles to inform vaccination strategies but can be costly and logistically challenging. Leveraging ...residual serum samples is one way to increase their feasibility. We subsampled 9854 residual sera from a 2016 national HIV survey in Zambia and tested these specimens for anti-measles and anti-rubella virus IgG antibodies using indirect enzyme immunoassays. We demonstrate innovative methods for sampling residual sera and analyzing seroprevalence data, as well as the value of seroprevalence estimates to understand and control measles and rubella. National measles and rubella seroprevalence for individuals younger than 50 years was 82.8% (95% CI 81.6, 83.9%) and 74.9% (95% CI 73.7, 76.0%), respectively. Despite a successful childhood vaccination program, measles immunity gaps persisted across age groups and districts, indicating the need for additional activities to complement routine immunization. Prior to vaccine introduction, we estimated a rubella burden of 96 congenital rubella syndrome cases per 100,000 live births. Residual samples from large-scale surveys can reduce the cost and challenges of conducting serosurveys, and multiple pathogens can be tested. Procedures to access quality specimens, ensure ethical approvals, and link sociodemographic data can improve the timeliness and value of results.
We present the detection of five planets—Kepler-62b, c, d, e, and f—of size 1.31, 0.54, 1.95, 1.61 and 1.41 Earth radii (R ⊕ ), orbiting a K2V star at periods of 5.7, 12.4, 18.2, 122.4, and 267.3 ...days, respectively. The outermost planets, Kepler-62e and -62f, are super-Earth-size (1.25 R ⊕ < planet radius < 2.0 R ⊕ ) planets in the habitable zone of their host star, respectively receiving 1.2 ± 0.2 times and 0.41 ± 0.05 times the solar flux at Earth's orbit. Theoretical models of Kepler-62e and -62f for a stellar age of ~7 billion years suggest that both planets could be solid, either with a rocky composition or composed of mostly solid water in their bulk.
Pathologic angiogenesis mediated by abnormally polarized macrophages plays a central role in common age-associated diseases such as atherosclerosis, cancer, and macular degeneration. Here we ...demonstrate that abnormal polarization in older macrophages is caused by programmatic changes that lead to reduced expression of ATP binding cassette transporter ABCA1. Downregulation of ABCA1 by microRNA-33 impairs the ability of macrophages to effectively efflux intracellular cholesterol, which in turn leads to higher levels of free cholesterol within senescent macrophages. Elevated intracellular lipid polarizes older macrophages to an abnormal, alternatively activated phenotype that promotes pathologic vascular proliferation. Mice deficient for Abca1, but not Abcg1, demonstrate an accelerated aging phenotype, whereas restoration of cholesterol efflux using LXR agonists or miR-33 inhibitors reverses it. Monocytes from older humans with age-related macular degeneration showed similar changes. These findings provide an avenue for therapeutic modulation of macrophage function in common age-related diseases.
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► Macrophage senescence impairs cholesterol efflux and promotes macular degeneration ► Senescent macrophages polarize to a proangiogenic, disease-promoting phenotype ► Macrophage cholesterol efflux is regulated by miR33 and its target ABCA1 ► Age-related decrease in macrophage cholesterol efflux is therapeutically reversible
Many individuals living in precarious housing or homelessness have multimorbid illnesses, including substance use, psychiatric, and neurological disorders. Movement disorders (MDs) associated ...substance use are amongst the poorly studied subtopics of drug-induced MDs. The aim of the present study was, therefore, to determine the proportion affected and severity of different signs of MDs, as well as their associations with substance use in a community-based sample of precariously housed and homeless individuals.
Participants were recruited from an impoverished urban neighborhood and were assessed for substance dependence and self-reported substance use (alcohol, cannabis, cocaine, methamphetamine, nicotine, and opioids), as well as for the severity of signs of MDs (akathisia, dyskinesia, dystonia, and parkinsonism). Adjusted regression models were used to estimate the associations of the severity of signs with the frequency of substance use over the past 4 weeks and with the baseline diagnosis of substance dependence.
The proportion of the sample with clinically relevant signs of MDs in any of the four categories was 18.6% (n = 401), and these participants demonstrated lower levels of functioning than those without signs. Of the different types of substance use, only methamphetamine (its frequency of use and dependence) was significantly associated with greater severity of overall signs of MDs. Frequency of methamphetamine use significantly interacted with age and sex, whereby older female participants exhibited the greatest overall severity with increased methamphetamine use. Of the different signs of MDs, methamphetamine use frequency was positively associated with the severity of trunk/limb dyskinesia and hypokinetic parkinsonism. Relative to no use, concurrent use of antipsychotics demonstrated lower severity of trunk/limb dyskinesia and greater severity of hypokinetic parkinsonism with methamphetamine use, and greater severity of dystonia with cocaine use.
Our study found a high proportion of MDs in a relatively young sample, and their severity was consistently associated with methamphetamine use, moderated by participant demographics and antipsychotic use. These disabling sequelae represent an important and understudied neurological condition that may affect quality of life and will require further study.
•Precariously housed and homeless individuals exhibited high rates of substance use.•Study subjects had high rates of movement disorders.•Methamphetamine use was associated with more severe movement disorders.•Concurrent methamphetamine use with antipsychotics affected movement disorders.
Effective conservation management interventions must combat threats and deliver benefits at costs that can be achieved within limited budgets. Considerable effort has focused on measuring the ...potential benefits of conservation interventions, but explicit quantification of the financial costs of implementation is rare. Even when costs have been quantified, haphazard and inconsistent reporting means published values are difficult to interpret. This reporting deficiency hinders progress toward a collective understanding of the financial costs of management interventions across projects and thus limits the ability to identify efficient solutions to conservation problems or attract adequate funding. We devised a standardized approach to describing financial costs reported for conservation interventions. The standards call for researchers and practitioners to describe the objective and outcome, context and methods, and scale of costed interventions, and to state which categories of costs are included and the currency and date for reported costs. These standards aim to provide enough contextual information that readers and future users can interpret the cost data appropriately. We suggest these standards be adopted by major conservation organizations, conservation science institutions, and journals so that cost reporting is comparable among studies. This would support shared learning and enhance the ability to identify and perform cost-effective conservation. Las intervenciones efectivas de manejo para la conservación deben combatir amenazas y proporcionar beneficios con costos que se pueden obtener con presupuestos limitados. Se han enfocado esfuerzos considerables para medir los beneficios potenciales de las intervenciones de conservación, pero es rara la cuantificación explícita de los costos financieros de la implementación. Aun cuando se han cuantificado los costos, los informes aleatorios e inconsistentes significa que los valores publicados son difíciles de entender. Esta deficiencia en los informes limita el progreso hacia un entendimiento colectivo de los costos financieros de las intervenciones de manejo y por lo tanto limita la habilidad de identificar soluciones eficientes a los problemas de conservación o de atraer financiamiento adecuado. Diseñamos un método estandarizado para describir los costos financieros reportados para las intervenciones para la conservación. Los estándares requieren que los investigadores y practicantes describan el objetivo y resultados, el contexto y los métodos y la escala de las intervenciones presupuestadas y que citen las categorías de costos incluidas y la divisa y fecha de los costos reportados. Estos estándares tratan de proporcionar suficiente información contextual para que los lectores y futuros usuarios puedan interpretar los datos de costos apropiadamente. Sugerimos que estos estándares sean adoptados por las principales organizaciones de conservación, las instituciones científicas y las revistas para que los informes de costos sean comparables entre estudios. Esto daría soporte al aprendizaje compartido y incrementar la habilidad para identificar y realizar conservación rentable. 有效的保护管理干预必须与其所受到的威胁作斗争，并且在有限预算内获得收益。现在有许多工作用于 衡量保护干预的潜在收益，却少有对措施实施的成本进行明确地量化。即使存在这样的量化，这些缺少规划、 前后不一致的分析报告也使得这些量化的结果难以被解释。这类报告的缺陷阻碍了进ー步对跨项目管理干预的 財政成本的综合认识，因此也限制了确定解决保护问题的有效措施和吸引到充足经费的能力。这里,我们册了 一种标准化的方法来描述保护干预的财政成本报告, 这套标准要求研究者和实践者描述目标和结果、背景和方 法、干预的规摸, 并说明包括了哪些类别的成本、报告成本所用的货币及日期。我们提出的标准旨在提供足够 的背景信息，以便读者和将来的使用者可以合理地解读这些成本数据。我们建议重要的保护组织、保护科学机 构和期刊采用这些标准，使得这些成本报告在不同研究中具有可比较性。这还有助于共同学习，提高认识和实施 高效益的保护管理的能力。
Aims
The COVID‐19 pandemic caused significant disruption to routine activity in primary care. Medication reviews are an important primary care activity ensuring safety and appropriateness of ...prescribing. A disruption could have significant negative implications for patient care. Using routinely collected data, our aim was first to describe codes used to record medication review activity and then to report the impact of COVID‐19 on the rates of medication reviews.
Methods
With the approval of NHS England, we conducted a cohort study of 20 million adult patient records in general practice, in‐situ using the OpenSAFELY platform. For each month, between April 2019 and March 2022, we report the percentage of patients with a medication review coded monthly and in the previous 12 months with breakdowns by regional, clinical and demographic subgroups and those prescribed high‐risk medications.
Results
In April 2019, 32.3% of patients had a medication review coded in the previous 12 months. During the first COVID‐19 lockdown, monthly activity decreased (−21.1% April 2020), but the 12‐month rate was not substantially impacted (−10.5% March 2021). The rate of structured medication review in the last 12 months reached 2.9% by March 2022, with higher percentages in high‐risk groups (care home residents 34.1%, age 90+ years 13.1%, high‐risk medications 10.2%). The most used medication review code was Medication review done 314530002 (59.5%).
Conclusions
There was a substantial reduction in the monthly rate of medication reviews during the pandemic but rates recovered by the end of the study period. Structured medication reviews were prioritized for high‐risk patients.
We present the first APOKASC catalog of spectroscopic and asteroseismic properties of 1916 red giants observed in the Kepler fields. The spectroscopic parameters provided from the Apache Point ...Observatory Galactic Evolution Experiment project are complemented with asteroseismic surface gravities, masses, radii, and mean densities determined by members of the Kepler Asteroseismology Science Consortium. We assess both random and systematic sources of error and include a discussion of sample selection for giants in the Kepler fields. Total uncertainties in the main catalog properties are of the order of 80 K in T sub(eff), 0.06 dex in M/H, 0.014 dex in log g, and 12% and 5% in mass and radius, respectively; these reflect a combination of systematic and random errors. Asteroseismic surface gravities are substantially more precise and accurate than spectroscopic ones, and we find good agreement between their mean values and the calibrated spectroscopic surface gravities. There are, however, systematic underlying trends with T sub(eff) and log g. Our effective temperature scale is between 0 and 200 K cooler than that expected from the infrared flux method, depending on the adopted extinction map, which provides evidence for a lower value on average than that inferred for the Kepler Input Catalog (KIC). We find a reasonable correspondence between the photometric KIC and spectroscopic APOKASC metallicity scales, with increased dispersion in KIC metallicities as the absolute metal abundance decreases, and offsets in T sub(eff) and log g consistent with those derived in the literature. We present mean fitting relations between APOKASC and KIC observables and discuss future prospects, strengths, and limitations of the catalog data.
We have used asteroseismology to determine fundamental properties for 66 Kepler planet-candidate host stars, with typical uncertainties of 3% and 7% in radius and mass, respectively. The results ...include new asteroseismic solutions for four host stars with confirmed planets (Kepler-4, Kepler-14, Kepler-23 and Kepler-25) and increase the total number of Kepler host stars with asteroseismic solutions to 77. A comparison with stellar properties in the planet-candidate catalog by Batalha et al. shows that radii for subgiants and giants obtained from spectroscopic follow-up are systematically too low by up to a factor of 1.5, while the properties for unevolved stars are in good agreement. We furthermore apply asteroseismology to confirm that a large majority of cool main-sequence hosts are indeed dwarfs and not misclassified giants. Using the revised stellar properties, we recalculate the radii for 107 planet candidates in our sample, and comment on candidates for which the radii change from a previously giant-planet/brown-dwarf/stellar regime to a sub-Jupiter size or vice versa. A comparison of stellar densities from asteroseismology with densities derived from transit models in Batalha et al. assuming circular orbits shows significant disagreement for more than half of the sample due to systematics in the modeled impact parameters or due to planet candidates that may be in eccentric orbits. Finally, we investigate tentative correlations between host-star masses and planet-candidate radii, orbital periods, and multiplicity, but caution that these results may be influenced by the small sample size and detection biases.
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