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\"In celebration of the 50th anniversary of the Apollo 11 landing, the endlessly-mysterious moon is explored in this reprint short science fiction anthology from award-winning editor and anthologist Neil Clarke ... On July 20, 1969, mankind made what had only years earlier seemed like an impossible leap forward: when Apollo 11 became the first manned mission to land on the moon, and Neil Armstrong the first person to step foot on the lunar surface. While there have only been a handful of new missions since, the fascination with our planet's satellite continues, and generations of writers and artists have imagined the endless possibilities of lunar life. From adventures in the vast gulf of space between the earth and the moon, to journeys across the light face to the dark side, to the establishment of permanent residences on its surface, science fiction has for decades given readers bold and forward-thinking ideas about our nearest interstellar neighbor and what it might mean to humankind, both now and in our future. [This book] collects the best stories written in the fifty years since mankind first stepped foot on the lunar surface, serving as a shining reminder that the moon is and always has been our most visible and constant example of all the infinite possibility of the wider universe\"-- Provided by publisher.

Low hand grip strength (HGS) is associated with several conditions, but its value outside of the older adult population is unclear. We sought to identify the most salient factors associated with HGS from an extensive list of candidate variables while stratifying by age and sex. We used data from the initial visit from the Project Baseline Health Study (N = 2502) which captured detailed demographic, occupational, social, lifestyle, and clinical data. We applied MI-LASSO using group methods to determine variables most associated with HGS out of 175 candidate variables. We performed analyses separately for sex and age (< 65 vs. ≥ 65 years). Race was associated with HGS to varying degrees across groups. Osteoporosis and osteopenia were negatively associated with HGS in female study participants. Immune cell counts were negatively associated with HGS for male participants ≥ 65 (neutrophils) and female participants (≥ 65, monocytes; < 65, lymphocytes). Most findings were age and/or sex group-specific; few were common across all groups. Several of the variables associated with HGS in each group were novel, while others corroborate previous research. Our results support HGS as a useful indicator of a variety of clinical characteristics; however, its utility varies by age and sex.

Though widely used, resting heart rate (RHR), as measured by a wearable device, has not been previously evaluated in a large cohort against a variety of important baseline characteristics. This study aimed to assess the validity of the RHR measured by a wearable device compared against the gold standard of ECG (electrocardiography), and assess the relationships between device-measured RHR and a broad range of clinical characteristics. The Project Baseline Health Study (PHBS) captured detailed demographic, occupational, social, lifestyle, and clinical data to generate a deeply phenotyped cohort. We selected an analysis cohort within it, which included participants who had RHR determined by both ECG and the Verily Study Watch (VSW). We examined the correlation between these simultaneous RHR measures and assessed the relationship between VSW RHR and a range of baseline characteristics, including demographic, clinical, laboratory, and functional assessments. From the overall PBHS cohort (N=2502), 875 (35%) participants entered the analysis cohort (mean age 50.9, SD 16.5 years; n=519, 59% female and n=356, 41% male). The mean and SD of VSW RHR was 66.6 (SD 11.2) beats per minute (bpm) for female participants and 64.4 (SD 12.3) bpm for male participants. There was excellent reliability between the two measures of RHR (ECG and VSW) with an intraclass correlation coefficient of 0.946. On univariate analyses, female and male participants had similar baseline characteristics that trended with higher VSW RHR: lack of health care insurance (both P<.05), higher BMI (both P<.001), higher C-reactive protein (both P<.001), presence of type 2 diabetes mellitus (both P<.001) and higher World Health Organization Disability Assessment Schedule (WHODAS) 2.0 score (both P<.001) were associated with higher RHR. On regression analyses, within each domain of baseline characteristics (demographics and socioeconomic status, medical conditions, vitals, physical function, laboratory assessments, and patient-reported outcomes), different characteristics were associated with VSW RHR in female and male participants. RHR determined by the VSW had an excellent correlation with that determined by ECG. Participants with higher VSW RHR had similar trends in socioeconomic status, medical conditions, vitals, laboratory assessments, physical function, and patient-reported outcomes irrespective of sex. However, within each domain of baseline characteristics, different characteristics were most associated with VSW RHR in female and male participants. ClinicalTrials.gov NCT03154346; https://clinicaltrials.gov/study/NCT03154346.

To evaluate remote participant engagement in a clinical study over time, based on data from the Project Baseline Health Study (PBHS), a hybrid in-person and virtual study. The PBHS enrolled 2,502 adult US residents from March 3, 2017 to April 26, 2019, with a ≤5-year follow-up. We summarized 4-year retention and rates of longitudinal patient-reported outcome survey completion. We investigated participant characteristics for their associations with quarterly remote survey completion using regression models. Of the total participants (  = 2,502), 94% remained enrolled after 4 years and 60% completed all annual visits; 2,490 participants stayed enrolled for at least one quarter. The median (IQR) number of remote electronic survey sets completed was 8 (3-12), of a possible 16. Age [odds ratio (OR), >70 vs. ≤30 years: 2.56; 95% CI: 2.24-2.94] and education (OR, advanced degree vs. ≤high school: 1.36; 95% CI: 1.22-1.52) were positively associated with remote survey completion. Participants with lower odds of completion were Black (OR vs. White: 0.73; 95% CI: 0.67-0.80), Hispanic (OR vs. non-Hispanic: 0.84; 95% CI: 0.77-0.93), or had at least mild symptoms of depression (OR vs. without: 0.90; 95% CI: 0.84-0.96) or anxiety (OR vs. without: 0.84; 95% CI: 0.78-0.90). Overall, 94% of PBHS participants remained enrolled after four years. Age, race, ethnicity, income, education, and symptomatic depression/anxiety were significantly associated with longitudinal remote questionnaire completion. These findings on engagement over time may inform future longitudinal study design. Clinicaltrials.gov, identifier (NCT03154346).

There are important gaps in knowledge of the optimal treatment of cystic fibrosis pulmonary exacerbations. Previous observational studies comparing inpatient with outpatient treatment have suffered from methodologic weaknesses, especially indication bias. We analyzed data from the Epidemiologic Study of Cystic Fibrosis using techniques to control for indication bias to determine whether there is an advantage to inpatient treatment of cystic fibrosis pulmonary exacerbations. We identified typical pulmonary exacerbations in patients ages 6 years and older during the 3-year observation period ending in 2005. In our primary analysis, we used the instrumental variables method, implemented using two-stage least squares regression, to evaluate the effect of the proportion of total time that intravenous treatment was administered on an inpatient (versus outpatient) basis on the likelihood of return of percent predicted forced expiratory volume in 1 second to greater than or equal to 90% of baseline post-treatment. We also evaluated two other indicators of treatment setting, three other measures of treatment response, and two alternative modeling techniques, and we also looked for differences between children and adults. Our final analysis included 4,497 pulmonary exacerbations in 2,773 individual patients at 75 sites. We calculated the mean proportion of intravenous treatment time that was provided in the hospital setting at each site. The median across sites was 0.581 (interquartile range, 0.396-0.753). The median treatment success rate across sites was 74.2% (interquartile range, 67.9 to 79.2%). Univariate analysis and two-stage least squares models showed a positive relationship between treatment success and proportion of inpatient treatment days. Our primary model revealed an absolute increase of 9.08% (95% confidence interval, 2.55-15.61; P = 0.006) in the achievement of a return of percent predicted forced expiratory volume in 1 second to greater than or equal to 90% of baseline comparing complete inpatient treatment with no inpatient treatment. Treatment response was not related to duration of intravenous therapy. Similar results were found for all our modeling techniques and outcomes. Patients with cystic fibrosis treated at sites with more reliance on inpatient treatment were more likely to achieve successful forced expiratory volume in 1 second recovery. There was no relationship between treatment duration and recovery of forced expiratory volume in 1 second.

Terminal erythroid differentiation in vertebrates is characterized by progressive heterochromatin formation and chromatin condensation and, in mammals, culminates in nuclear extrusion. To date, although mechanisms regulating avian erythroid chromatin condensation have been identified, little is known regarding this process during mammalian erythropoiesis. To elucidate the molecular basis for mammalian erythroblast chromatin condensation, we used Friend virus-infected murine spleen erythroblasts that undergo terminal differentiation in vitro. Chromatin isolated from early and late-stage erythroblasts had similar levels of linker and core histones, only a slight difference in nucleosome repeats, and no significant accumulation of known developmentally regulated architectural chromatin proteins. However, histone H3(K9) dimethylation markedly increased while histone H4(K12) acetylation dramatically decreased and became segregated from the histone methylation as chromatin condensed. One histone deacetylase, HDAC5, was significantly upregulated during the terminal stages of Friend virus-infected erythroblast differentiation. Treatment with histone deacetylase inhibitor, trichostatin A, blocked both chromatin condensation and nuclear extrusion. Based on our data, we propose a model for a unique mechanism in which extensive histone deacetylation at pericentromeric heterochromatin mediates heterochromatin condensation in vertebrate erythroblasts that would otherwise be mediated by developmentally-regulated architectural proteins in nucleated blood cells.

The pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to a rapid response by the scientific community to further understand and combat its associated pathologic etiology. A focal point has been on the immune responses mounted during the acute and post-acute phases of infection, but the immediate post-diagnosis phase remains relatively understudied. We sought to better understand the immediate post-diagnosis phase by collecting blood from study participants soon after a positive test and identifying molecular associations with longitudinal disease outcomes. Multi-omic analyses identified differences in immune cell composition, cytokine levels, and cell subset-specific transcriptomic and epigenomic signatures between individuals on a more serious disease trajectory (Progressors) as compared to those on a milder course (Non-progressors). Higher levels of multiple cytokines were observed in Progressors, with IL-6 showing the largest difference. Blood monocyte cell subsets were also skewed, showing a comparative decrease in non-classical CD14-CD16+ and intermediate CD14+CD16+ monocytes. Additionally, in the lymphocyte compartment, CD8+ T effector memory cells displayed a gene expression signature consistent with stronger T cell activation in Progressors. Importantly, the identification of these cellular and molecular immune changes occurred at the early stages of COVID-19 disease. These observations could serve as the basis for the development of prognostic biomarkers of disease risk and interventional strategies to improve the management of severe COVID-19.The pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to a rapid response by the scientific community to further understand and combat its associated pathologic etiology. A focal point has been on the immune responses mounted during the acute and post-acute phases of infection, but the immediate post-diagnosis phase remains relatively understudied. We sought to better understand the immediate post-diagnosis phase by collecting blood from study participants soon after a positive test and identifying molecular associations with longitudinal disease outcomes. Multi-omic analyses identified differences in immune cell composition, cytokine levels, and cell subset-specific transcriptomic and epigenomic signatures between individuals on a more serious disease trajectory (Progressors) as compared to those on a milder course (Non-progressors). Higher levels of multiple cytokines were observed in Progressors, with IL-6 showing the largest difference. Blood monocyte cell subsets were also skewed, showing a comparative decrease in non-classical CD14-CD16+ and intermediate CD14+CD16+ monocytes. Additionally, in the lymphocyte compartment, CD8+ T effector memory cells displayed a gene expression signature consistent with stronger T cell activation in Progressors. Importantly, the identification of these cellular and molecular immune changes occurred at the early stages of COVID-19 disease. These observations could serve as the basis for the development of prognostic biomarkers of disease risk and interventional strategies to improve the management of severe COVID-19.

Introduction The recommended dosage range for sodium oxybate (SXB) among adults with narcolepsy is 6-9g per night orally, divided into 2 equal doses. The objective of this study was to describe real-world dosing of SXB among adults with narcolepsy. Methods The Nexus Narcolepsy Registry is an ongoing, self-reported online registry of adults diagnosed with narcolepsy. The study identified SXB users who had reported dosage data and compared those currently taking SXB vs those who previously discontinued. Of current users, those taking SXB <3 months (hereafter “new users”) vs ≥3 months (hereafter “established users”) also were compared. The survey assessed once-nightly or twice-nightly SXB dosing across the dose range (<4.5g, 4.5-<6g, 6-<9g, 9g, >9g), and equally-divided (1st dose=2nd dose) vs asymmetric dosing (1st dose≠2nd dose). Descriptive analyses and t tests assessed sample characteristics and dosing patterns. All P values are uncontrolled for multiplicity, hence, are nominal. Results Among all participants reporting SXB use (n=365), 65% were current users and 95% took SXB twice nightly. Average total nightly dose (standard deviation) was 7g (±1.9) and 3.6g (±0.9) for twice-nightly and once-nightly dosing, respectively. Among those who took SXB twice nightly, the total nightly dose was lower in those who discontinued vs current users (5.9g ±2.1 vs 7.6g ±1.6; P<0.001) and lower in new users vs established users (6.5g ±1.8 vs 7.7g ±1.5; P<0.001). Among all SXB users, 66% reported doses within the recommended dosage range of 6-9g per night; 80% of current users and 40% of discontinued users took 6-9g per night. Nearly 30% of all SXB users, 16% of current users, and 55% of discontinued users took <6g per night. Among all SXB users, 84% reported equally-divided dosing. For current new users and current established users, 96% and 83%, respectively, reported equally-divided dosing. Conclusion Among SXB users in the Nexus Narcolepsy Registry, the majority reported taking SXB twice nightly, with the total nightly dose equally divided. 17% of current established users reported asymmetric dosing, and 5% of all SXB users reported once-nightly dosing. Support (If Any) Jazz Pharmaceuticals

Repair of bulky DNA adducts by the nucleotide excision repair （NER） pathway is one of the more versatile DNA repair pathways for the removal of DNA lesions. There are two subsets of the NER pathway, global genomic-NER （GG- NER） and transcription-coupled NER （TC-NER）, which differ only in the step involving recognition of the DNA lesion. Following recognition of the damage, the sub-pathways then converge for the incision/excision steps and subsequent gap filling and ligation steps. This review will focus on the GGR sub-pathway of NER, while the TCR sub-pathway will be covered in another article in this issue. The ability of the NER pathway to repair a wide array of adducts stems, in part, from the mechanisms involved in the initial recognition step of the damaged DNA and results in NER impacting an equally wide array of human physiological responses and events. In this review, the impact of NER on carcinogenesis, neurological function, sensitivity to environmental factors and sensitivity to cancer therapeutics will be discussed. The knowledge generated in our understanding of the NER pathway over the past 40 years has resulted from advances in the fields of animal model systems, mammalian genetics and in vitro biochemistry, as well as from reconstitution studies and structural analyses of the proteins and enzymes that participate in this pathway. Each of these avenues of research has contributed significantly to our understanding of how the NER pathway works and how alterations in NER activity, both positive and negative, influence human biology.

Microbiota studies of Aedes aegypti and other mosquitoes generally focus on the bacterial communities found in adult female midguts. However, other compartments of the digestive tract maintain communities of bacteria which remain almost entirely unstudied. For example, the Dipteran crop is a food storage organ, but few studies have looked at the microbiome of crops in mosquitoes, and only a single previous study has investigated the crop in Ae . aegypti . In this study, we used both culture-dependent and culture-independent methods to compare the bacterial communities in midguts and crops of laboratory reared Ae . aegypti . Both methods revealed a trend towards higher abundance, but also higher variability, of bacteria in the midgut than the crop. When present, bacteria from the genus Elizabethkingia (family Weeksellaceae) dominated midgut bacterial communities. In crops, we found a higher diversity of bacteria, and these communities were generally dominated by acetic acid bacteria (family Acetobacteriaceae) from the genera Tanticharoenia and Asaia . These three taxa drove significant community structure differences between the tissues. We used FAPROTAX to predict the metabolic functions of these communities and found that crop bacterial communities were significantly more likely to contain bacteria capable of methanol oxidation and methylotrophy. Both the presence of acetic acid bacteria (which commonly catabolize sugar to produce acetic acid) and the functional profile that includes methanol oxidation (which is correlated with bacteria found with natural sources like nectar) may relate to the presence of sugar, which is stored in the mosquito crop. A better understanding of what bacteria are present in the digestive tract of mosquitoes and how these communities assemble will inform how the microbiota impacts mosquito physiology and the full spectrum of functions provided by the microbiota. It may also facilitate better methods of engineering the mosquito microbiome for vector control or prevention of disease transmission.