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Background: The human microbiome can contribute to pathogeneses of many complex diseases by mediating disease-leading causal pathways. However, standard mediation analysis methods are not adequate to analyze the microbiome as a mediator due to the excessive number of zero-valued sequencing reads in the data and that the relative abundances have to sum to one. The two main challenges raised by the zero-inflated data structure are: (a) disentangling the mediation effect induced by the point mass at zero; and (b) identifying the observed zero-valued data points that are not zero (i.e., false zeros). Methods: We develop a novel marginal mediation analysis method under the potential-outcomes framework to address the issues. We also show that the marginal model can account for the compositional structure of microbiome data. Results: The mediation effect can be decomposed into two components that are inherent to the two-part nature of zero-inflated distributions. With probabilistic models to account for observing zeros, we also address the challenge with false zeros. A comprehensive simulation study and the application in a real microbiome study showcase our approach in comparison with existing approaches. Conclusions: When analyzing the zero-inflated microbiome composition as the mediators, MarZIC approach has better performance than standard causal mediation analysis approaches and existing competing approach. [ABSTRACT FROM AUTHOR]

Our first targets in the search for signs of life are orbiting nearby M stars, such as the planets in the Proxima Centauri, Ross-128, LHS-1140, and TRAPPIST-1 systems. Future ground-based discoveries, and those from the TESS mission, will provide additional close-by targets. However, young M stars tend to be very active, flaring frequently and causing UV fluxes on the surfaces of HZ planets to become biologically harmful. Common UV-protection methods used by life (e.g. living underground, or underwater) would make a biosphere harder to detect. However, photoprotective biofluorescence, 'up-shifting' UV to longer, safer wavelengths, could increase a biosphere's detectability. Here we model intermittent emission at specific wavelengths in the visible spectrum caused by biofluorescence as a new temporal biosignature for planets around active M stars. We use the absorption and emission characteristics of common coral fluorescent pigments and proteins to create model spectra and colours for an Earth-like planet in such a system, accounting for different surface features, atmospheric absorption, and cloud cover. We find that for a cloud-free planet biofluorescence could induce a temporary change in brightness that is significantly higher than the reflected flux alone, causing up to two orders-of-magnitude change in planet–star contrast, compared to a non-fluorescent state, if the surface is fully covered by a highly efficient fluorescent biosphere. Hence, UV-flare induced biofluorescence presents previously unexplored possibilities for a new temporal biosignature that could be detectable by instruments like those planned for the extremely large telescope and could reveal hidden biospheres. [ABSTRACT FROM AUTHOR]

The closest potentially habitable worlds outside our Solar system orbit a different kind of star than our Sun: smaller red dwarf stars. Such stars can flare frequently, bombarding their planets with biologically damaging high-energy UV radiation, placing planetary atmospheres at risk of erosion and bringing the habitability of these worlds into question. However, the surface UV flux on these worlds is unknown. Here we show the first models of the surface UV environments of the four closest potentially habitable exoplanets: Proxima-b, TRAPPIST-1e, Ross-128b, and LHS-1140b assuming different atmospheric compositions, spanning Earth-analogue to eroded and anoxic atmospheres and compare them to levels for Earth throughout its geological evolution. Even for planet models with eroded and anoxic atmospheres, surface UV radiation remains below early Earth levels, even during flares. Given that the early Earth was inhabited, we show that UV radiation should not be a limiting factor for the habitability of planets orbiting M stars. Our closest neighbouring worlds remain intriguing targets for the search for life beyond our Solar system. [ABSTRACT FROM AUTHOR]

In this paper, we analyse a new possible biological surface feature for habitable worlds orbiting other stars: biofluorescence. High ultraviolet (UV) and blue radiation fluxes drive the strongest biofluorescence in terrestrial fluorescent pigments and proteins. F stars emit more blue and UV radiation than the Sun, while planets and exomoons orbiting such stars remain in the habitable zone for 2–4 Gyr; a time span that could allow a complex biosphere to develop. Therefore, we propose biofluorescence as a new surface biosignature for F star planets. We investigate how the extra emission from surface fluorescence could cause observable signals at specific wavelengths in the visible spectrum. Using the absorption and emission characteristics of common coral fluorescent pigments and proteins, we simulate the increased emission at specific visible wavelengths caused by strong fluorescence, accounting for the effects of different (non-fluorescent) surface features, atmospheric absorption and cloud cover. Our model shows that exoplanets with a fluorescent biosphere could have characteristic surface colours that allow the presence of surface life to be inferred from observations with upcoming telescopes. [ABSTRACT FROM AUTHOR]

The high reflection of land vegetation in the near-infrared, the vegetation red edge (VRE), is often cited as a spectral biosignature for surface vegetation on exoplanets. The VRE involves only a few percentage change in reflectivity for a disk-integrated observation of present-day Earth. Here we show that the strength of Earth's VRE has increased over the past ∼500 million years of land plant evolution and may continue to increase as solar luminosity increases and the planet warms, until either vegetation coverage is reduced, or the planet's atmosphere becomes opaque to light reflected off the surface. Early plants such as mosses and liverworts, which dominated the land 500–400 million years ago, produce a weaker VRE, approximately half as strong as that of modern vegetation. We explore how the changes in land plants, as well as geological changes such as ice coverage during ice ages and interglacial periods, influence the detectability of the VRE through Earth's geological past. Our results show that the VRE has varied through the evolutionary history of land plants on Earth and could continue to change into the future if hotter climate conditions became dominant, encouraging the spread of vegetation. Our findings suggest that older and hotter Earth-like planets are good targets for the search for a VRE signature. In addition, hot exoplanets and dry exoplanets with some water could be the best targets for a successful vegetation biosignature detection. As well as a strong red edge, lower cloud fractions and low levels of atmospheric water vapor on such planets could make it easier to detect surface features in general. [ABSTRACT FROM AUTHOR]

With the discovery of rocky planets in the temperate habitable zone (HZ) of the closeby cool star TRAPPIST-1, the question of whether such planets could harbour life arises. Habitable planets around red dwarf stars can orbit in radiation environments that can be life-sterilizing. Ultraviolet (UV) flares from these stars are more frequent and intense than solar flares. Additionally, their temperate HZs are closer to the star. Here we present UV surface environment models for TRAPPIST-1's HZ planets and explore the implications for life. TRAPPIST-1 has high X-ray/extreme-ultraviolet activity, placing planetary atmospheres at risk from erosion. If a dense Earth-like atmosphere with a protective ozone layer existed on planets in the HZ of TRAPPIST-1, UV surface environments would be similar to the present-day Earth. However, an eroded or an anoxic atmosphere would allow more UV to reach the surface, making surface environments hostile even to highly UV tolerant terrestrial extremophiles. If future observations detect ozone in the atmospheres of any of the planets in the HZ of TRAPPIST-1, these would be interesting targets for the search for surface life. We anticipate our assay to be a starting point for in-depth exploration of stellar and atmospheric observations of the TRAPPIST-1 planets to constrain their UV surface habitability. [ABSTRACT FROM AUTHOR]

Earth will become uninhabitable within 2-3 Gyr as a result of the increasing luminosity of the Sun changing the boundaries of the habitable zone (HZ). Predictions about the future of habitable conditions on Earth include declining species diversity and habitat extent, ocean loss, and changes to geochemical cycles. Testing these predictions is difficult, but the discovery of a planet that is an analogue to future Earth could provide the means to test them. This planet would need to have an Earth-like biosphere history and to be approaching the inner edge of the HZ at present. Here, we assess the possibility of finding such a planet and discuss the benefits of analyzing older Earths. Finding an old-Earth analogue in nearby star systems would be ideal, because this would allow for atmospheric characterization. Hence, as an illustrative example, G stars within 10 pc of the Sun are assessed as potential old-Earth-analog hosts. Six of these represent good potential hosts. For each system, a hypothetical Earth analogue is placed at locations within the continuously habitable zone (CHZ) that would allow enough time for Earth-like biosphere development. Surface temperature evolution over the host star's main sequence lifetime (assessed by using a simple climate model) is used to determine whether the planet would be in the right stage of its late-habitable lifetime to exhibit detectable biosignatures. The best candidate, in terms of the chances of planet formation in the CHZ and of biosignature detection, is 61 Virginis. However, planet formation studies suggest that only a small fraction (0.36%) of G stars in the solar neighborhood could host an old-Earth analogue. If the development of Earth-like biospheres is rare, requiring a sequence of low-probability events to occur, biosphere evolution models suggest they are rarer still, with only thousands being present in the Galaxy as a whole. Key Words: Extrasolar terrestrial planets-Habitable zone-Planetary environments-Habitability. Astrobiology 15, 400-411. [ABSTRACT FROM AUTHOR]

Abstract: The habitable zone (HZ) is conventionally the thin shell of space around a star within which liquid water is thermally stable on the surface of an Earth-like planet (Kasting et al., 1993). However, life on Earth is not restricted to the surface and includes a “deep biosphere” reaching several km in depth. Similarly, subsurface liquid water maintained by internal planetary heat could potentially support life well outside conventional HZs. We introduce a new term, subsurface-habitability zone (SSHZ) to denote the range of distances from a star within which rocky planets are habitable at any depth below their surfaces up to a stipulated maximum, and show how SSHZs can be estimated from a model relating temperature, depth and orbital distance. We present results for Earth-like, Mars-like and selected extrasolar terrestrial planets, and conclude that SSHZs are several times wider and include many more planets than conventional surface-based habitable zones. [Copyright &y& Elsevier]

The generation of induced pluripotent stem (iPS) cells presents a challenge to normal developmental processes. The low efficiency and heterogeneity of most methods have hindered understanding of the precise molecular mechanisms promoting, and roadblocks preventing, efficient reprogramming. Although several intermediate populations have been described, it has proved difficult to characterize the rare, asynchronous transition from these intermediate stages to iPS cells. The rapid expansion of minor reprogrammed cells in the heterogeneous population can also obscure investigation of relevant transition processes. Understanding the biological mechanisms essential for successful iPS cell generation requires both accurate capture of cells undergoing the reprogramming process and identification of the associated global gene expression changes. Here we demonstrate that in mouse embryonic fibroblasts, reprogramming follows an orderly sequence of stage transitions, marked by changes in the cell-surface markers CD44 and ICAM1, and a Nanog-enhanced green fluorescent protein (Nanog-eGFP) reporter. RNA-sequencing analysis of these populations demonstrates two waves of pluripotency gene upregulation, and unexpectedly, transient upregulation of several epidermis-related genes, demonstrating that reprogramming is not simply the reversal of the normal developmental processes. This novel high-resolution analysis enables the construction of a detailed reprogramming route map, and the improved understanding of the reprogramming process will lead to new reprogramming strategies. [ABSTRACT FROM AUTHOR]

The potential for Earth-like planets within binary/multiple-star systems to host photosynthetic life was evaluated by modeling the levels of photosynthetically active radiation (PAR) such planets receive. Combinations of M and G stars in (i) close-binary systems; (ii) wide-binary systems, and (iii) three-star systems were investigated, and a range of stable radiation environments were found to be possible. These environmental conditions allow for the possibility of familiar, but also more exotic, forms of photosynthetic life, such as IR photosynthesizers and organisms that are specialized for specific spectral niches. Key Words: Astrobiology-Extrasolar terrestrial planets-Extraterrestrial life-Photosynthesis. Astrobiology 12, 115-124. [ABSTRACT FROM AUTHOR]

Direct reprogramming of somatic cells to a pluripotent state, substantiated only three years prior, is one of the most rapidly developing areas of stem cell research. The generation of patient-derived pluripotent cells applicable to disease modelling, drug screening, toxicology tests and, ultimately, autologous cell-based therapies, has the potential to revolutionize medicine. Since 2006, when Takahashi and Yamanaka first reported the generation of induced pluripotent stem cells from murine fibroblasts via retroviral transduction of a defined set of transcription factors, various new methods have been developed to refine and improve reprogramming technology. This review focusses on these evolving strategies to generate genetically unmodified or reprogramming factor-free iPSCs. [Copyright &y& Elsevier]

Kimball, Scot R., James P. O'Malley, Joshua C. Anthony, Stephen J. Crozier, and Leonard S. Jefferson. Assessment of biomarkers of protein anabolism in skeletal muscle during the life span of the rat: sarcopenia despite elevated protein synthesis. Am J Physiol Endocrinol Metab 287: E772-E780, 2004. First published June 8, 2004; 10.1152/ajpendo.00535.2003.—Loss of muscle strength is a principal factor in the development of physical frailty, a condition clinically associated with increased risk of bone fractures, impairments in the activities of daily living, and loss of independence in older humans. A primary determinant in the decline in muscle strength that occurs during aging is a loss of muscle mass, which could occur through a reduction in the rate of protein synthesis, an elevation in protein degradation, or a combination of both. In the present study, rates of protein synthesis and the relative expression and function of various biomarkers involved in the initiation of mRNA translation in skeletal muscle were examined at different times throughout the life span of the rat. It was found that between 1 and 6 mo of age, body weight increased fourfold. However, by 6 mo, gastrocnemius protein synthesis and RNA content per gram of muscle were lower than values observed in l-mo-old rats. Moreover, the relative expression of two proteins involved in the binding of initiator methionyl-tRNA to the 40S ribosomal subunit, eukaryotic initiation factors (eIF)2 and eIF2B, as well as the 70-kDa ribosomal protein S6 kinase, S6K1, was lower at 6 mo compared with 1 mo of age. Muscle mass, protein synthesis, and the aforementioned biomarkers remained unchanged until ∼21 mo. Between 21 and 24 mo of age, muscle mass decreased precipitously. Surprisingly, during this period protein synthesis, relative RNA content, eIF2B activity, relative eIF2 expression, and S6K1 phosphorylation all increased. The results are consistent with a model wherein protein synthesis is enhanced during aging in a futile attempt to maintain muscle mass. [ABSTRACT FROM AUTHOR]

Presents information on a study conducted on rats which focused on the stability of acetylcholine receptors in relation to exogenous Adenosine Triphosphate(ATP) and its reversal by Cyclic Adenosine 3'-5' Phosphate (cAMP) and calcium. Objectives of the study; Methods and materials used in experiments.

Mathematics Support Centres are available in the majority of Higher Education Institutions in Ireland and the UK. Whilst the online presence of these centres appears to be increasing, there is little research to date which considers its breadth or effectiveness. In this paper we consider the results of a survey on the online presence of support centres in Ireland and the UK. We discuss the opportunities that arise from such a presence, the challenges that exist and what the results of the survey mean for individual practitioners and the wider mathematics support community. [ABSTRACT FROM AUTHOR]

Background: Fewer than half of the US population has an advance healthcare directive. Hospitalizations offer a key opportunity for clinicians to engage patients in advance care planning (ACP) conversations. Guidelines suggest screening for the presence of "serious illness" but do not further specify how to prioritize the 12.4 million patients hospitalized each year. Objective: To establish a normative standard for prioritizing hospitalized patients for ACP conversations. Design and Setting: A modified Delphi study, with three iterative rounds of online surveys. Participants: Multi-disciplinary group of US-based clinicians with research and practical expertise in ACP. Main Measures: Indirect and direct elicitation of short-term and 1-year risk of mortality that prompt experts to prioritize ACP conversations for hospitalized adults. Main results: Fifty-seven of 108 (52%) candidate panelists completed round 1, and 47 completed rounds 2 and 3. Panelists were primarily physicians (84%), with significant experience (mean years 23 [SD 9.8]), who either taught (55%) and/or performed research about ACP (55%). In round 1, > 70% of panelists agreed that all hospitalized adults ≥ 65 years should have an ACP conversation before discharge, but disagreed about the timing and content of the conversation. By round 3, > 70% of participants agreed that patients with either high (> 10%) short-term or high (≥ 34%) 1-year risk of mortality should have a goals of care conversation (i.e., focused on preferences for near-term treatment), while patients with low (≤ 10%) short-term and low (< 19%) 1-year risk of mortality warranted an ACP conversation (i.e., focused on preferences for future care) before discharge. Limitations: Use of case vignettes to elicit clinician judgment; response rate. Conclusions: Panelists agreed that clinicians should have an ACP conversation with all hospitalized adults over 65 years in an ACP conversation, adjusting the content and timing of the conversation conditional on the patient's risk of short-term and 1-year mortality. [ABSTRACT FROM AUTHOR]

Objectives: Graphic display formats are often used to enhance health information. Yet limited attention has been paid to graph literacy in people of lower education and lower socioeconomic status (SES). This study aimed to: 1) examine the relationship between graph literacy, numeracy, health literacy and sociodemographic characteristics in a Medicaid-eligible population 2) determine the impact of graph literacy on comprehension and preference for different visual formats. Methods: We conducted a cross-sectional online survey among people in the US on Medicaid, and of presumed lower education and SES. Results: The mean graph literacy score among 436 participants was 1.47 (SD 1.05, range: 0 to 4). Only graph literacy was significantly associated with overall comprehension (p <.001). Mean comprehension scores were highest for the table format (1.91), closely followed by bar graph (1.85) and icon array (1.80). Information comprehension was aligned with preference scores. Conclusions: Graph literacy in a Medicaid-eligible population was lower than previous estimates in the US. Tables were better understood, with icon arrays yielding the lowest score. Preferences aligned with comprehension. Practice implications: It may be necessary to reconsider the use of graphic display formats when designing information for people with lower educational levels. Further research is needed. [ABSTRACT FROM AUTHOR]

In this paper, we consider the changes to mathematics learning support (MLS) at Maynooth University due to the COVID-19 pandemic, including the provision of novel online study groups aimed at increasing student engagement and interaction. We briefly outline the local, national and international impact of COVID-19 on MLS and then focus on the results of a student survey. Respondents who regularly used online MLS were broadly positive about their experiences. They cited, in particular, the influence of tutors and the scheduled study groups, which provided structure and motivation as well as the opportunity to work with others and ask questions in less intimidating small groups. However, some respondents highlighted factors that impacted negatively on their engagement. These included low attendance or interaction from peers, timetabling issues or busy schedules, lack of awareness of the details of the services and increased feelings of discomfort and anxiety in an online environment. We consider how this student feedback may influence our future online and in-person supports. [ABSTRACT FROM AUTHOR]

Stem cells are capable of unlimited proliferation but can be induced to form brain cells. Factors that specifically regulate human development are poorly understood. We found that human stem cells expressed high levels of the envelope protein of an endogenized human-specific retrovirus (HERV-K, HML-2) from loci in chromosomes 12 and 19. The envelope protein was expressed on the cell membrane of the stem cells and was critical inmaintaining the stemness via interactions with CD98HC, leading to triggering of human-specific signaling pathways involving mammalian target of rapamycin (mTOR) and lysophosphatidylcholine acyltransferase (LPCAT1)-mediated epigenetic changes. Down-regulation or epigenetic silencing of HML-2 env resulted in dissociation of the stem cell colonies and enhanced differentiation along neuronal pathways. Thus HML-2 regulation is critical for human embryonic and neurodevelopment, while it's dysregulation may play a role in tumorigenesis and neurodegeneration. [ABSTRACT FROM AUTHOR]

This letter comments on the letter by Gwen Thomas et al. in this issue. [ABSTRACT FROM AUTHOR]

Habitability is a widely used word in the geoscience, planetary science, and astrobiology literature, but what does it mean? In this review on habitability, we define it as the ability of an environment to support the activity of at least one known organism. We adopt a binary definition of 'habitability' and a 'habitable environment.' An environment either can or cannot sustain a given organism. However, environments such as entire planets might be capable of supporting more or less species diversity or biomass compared with that of Earth. A clarity in understanding habitability can be obtained by defining instantaneous habitability as the conditions at any given time in a given environment required to sustain the activity of at least one known organism, and continuous planetary habitability as the capacity of a planetary body to sustain habitable conditions on some areas of its surface or within its interior over geological timescales. We also distinguish between surface liquid water worlds (such as Earth) that can sustain liquid water on their surfaces and interior liquid water worlds, such as icy moons and terrestrial-type rocky planets with liquid water only in their interiors. This distinction is important since, while the former can potentially sustain habitable conditions for oxygenic photosynthesis that leads to the rise of atmospheric oxygen and potentially complex multicellularity and intelligence over geological timescales, the latter are unlikely to. Habitable environments do not need to contain life. Although the decoupling of habitability and the presence of life may be rare on Earth, it may be important for understanding the habitability of other planetary bodies. Key Words: Habitability-Exoplanets-Habitat-Niche-Mars-Exoplanets. Astrobiology 16, 89-117. [ABSTRACT FROM AUTHOR]

Early in its history, Earth's surface developed from an uninhabitable magma ocean to a place where life could emerge. The first organisms, lacking ion transporters, fixed the composition of their cradle environment in their intracellular fluid. Later, though life adapted and spread, it preserved some qualities of its initial environment within. Modern prokaryotes could thus provide insights into the conditions of early Earth and the requirements for the emergence of life. In this work, we constrain Earth's life-forming environment through detailed analysis of prokaryotic intracellular fluid. Rigorous assessment of the constraints placed on the early Earth environment by intracellular liquid will provide insight into the conditions of abiogenesis, with implications not only for our understanding of early Earth but also the formation of life elsewhere in the Universe. Key Words: Astrobiology-Early Earth-Hadean-Origin of life. Astrobiology 13, 294-302. [ABSTRACT FROM AUTHOR]

Background: Racial/ethnic disparities exist in the prevalence and outcomes of diabetes and hypertension in the U.S. A better understanding of the health beliefs and experiences of non-Hispanic Blacks and Latinos with these diseases could help to improve their care outcomes.Methods: We conducted eight focus groups stratified by participants' race/ethnicity, with 34 non-Hispanic Blacks and Latinos receiving care for diabetes and/or hypertension in one of 7 community health centers in Boston. Focus groups were designed to determine participants' levels of understanding about their chronic illness, assess their barriers to the management of their illness, and inquire about interventions they considered may help achieve better health outcomes.Results: Among both groups of participants, nutrition (traditional diets), genetics and environmental stress (e.g. neighborhood crime and poor conditions) were described as primary contributors to diabetes and hypertension. Unhealthy diets were reported as being a major barrier to disease management. Participants also believed that they would benefit from attending groups on management and education for their conditions that include creative ways to adopt healthy foods that complement their ethnic diets, exercise opportunities, and advice on how to prevent disease manifestation among family members.Conclusions: Interactive discussion groups focused on lifestyle modification and disease management should be created for patients to learn more about their diseases. Future research evaluating the effectiveness of interactive diabetes and hypertension groups that apply patient racial/ethnic traditions should be considered. [ABSTRACT FROM AUTHOR]

The thermophilic filamentous fungus Talaromyces emersonii secretes a variety of hydrolytic enzymes that are of interest for processing of biomass into fuel. Many carbohydrases have been isolated and characterized from this fungus, but no studies had been performed on peptidases. In this study, two acid-acting endopeptidases were isolated and characterized from the culture filtrate of T. emersonii. One of these enzymes was identified as a member of the recently classified glutamic peptidase family and was subsequently named T. emersonii glutamic peptidase 1 (TGP1). The second enzyme was identified as an aspartyl peptidase (PEP1). TGP1 was cloned and sequenced and shown to exhibit 64 and 47% protein identity to peptidases from Aspergillus niger and Scytalidium lignocolum, respectively. Substrate profiling of 16 peptides determined that TGP1 has broad specificity with a preference for large residues in the P1 site, particularly Met, Gln, Phe, Lys, Glu, and small amino acids at P1' such as Ala, Gly, Ser, or Thr. This enzyme efficiently cleaves an internally quenched fluorescent substrate containing the zymogen activation sequence (kcat/Km = 2 × 105 M-1 s-1). Maximum hydrolysis occurs at pH 3.4 and 50 °C. The reaction is strongly inhibited by a transition state peptide analog, TA1 (Ki = 1.5 nM), as well as a portion of the propeptide sequence, PT1 (Ki = 32 nM). Ex vivo studies show that hyphal extension of T. emersonii in complex media is unaffected by the aspartyl peptidase inhibitor pepstatin but is inhibited by TA1 and PT1. This study provides insight into the functional role of the glutamic peptidase TGP1 for growth of T. emersonii. [ABSTRACT FROM AUTHOR]

The article reports on the study on the quality of care for the treatment of acute medical conditions in hospitals in the U.S. Patients are more likely to receive high-quality of care in not-for-profit hospitals and in hospitals with high registered nurse staffing ratios and more investment in technology. Based on the research, policy makers must evaluate the effect of alternative payment approaches on quality.

Context Although vascular brachytherapy is the only approved therapy for restenosis following bare-metal stent implantation, drug-eluting stents are now being used. Data on the relative merits of each are limited. Objective To determine the safety and efficacy of the sirolimus-eluting stent compared with vascular brachytherapy for the treatment of patients with restenosis within a bare-metal stent. Design, Setting, and Patients Prospective, multicenter, randomized trial of 384 patients with in-stent restenosis who were enrolled between February 2003 and July 2004 at 26 academic and community medical centers. Data presented represent all follow-up as of June 30, 2005. Interventions Vascular brachytherapy (n = 125) or the sirolimus-eluting stent (n = 259). Main Outcome Measure Target vessel failure (cardiac death, myocardial infarction, or target vessel revascularization) at 9 months postprocedure. Results Baseline patient characteristics were well matched. Lesion length was similar between vascular brachytherapy and sirolimus-eluting stent patients (mean [SD], 16.76 [8.55] mm vs 17.22 [7.97] mm, respectively; P = .61). Procedural success was 99.2% (124/125) in the vascular brachytherapy group and 97.3% (250/257) in the sirolimus-eluting stent group (P = .28). The rate of target vessel failure was 21.6% (27/125) with vascular brachytherapy and 12.4% (32/259) with the sirolimus-eluting stent (relative risk [RR], 1.7; 95% confidence interval [CI], 1.1-2.8; P = .02). Target lesion revascularization was required in 19.2% (24/125) of the vascular brachytherapy group and 8.5% (22/259) of the sirolimus-eluting stent group (RR, 2.3 [95% CI, 1.3-3.9]; P = .004). At follow-up angiography, the rate of binary angiographic restenosis for the analysis segment was 29.5% (31/105) for the vascular brachytherapy group and 19.8% (45/227) for the sirolimus-eluting stent group (RR, 1.5 [95% CI, 1.0-2.2]; P = .07). Compared with the vascular brachytherapy group, minimal lumen diameter was larger in the sirolimus-eluting stent group at 6-month follow-up (mean [SD], 1.52 [0.63] mm vs 1.80 [0.63] mm; P<.001), reflecting greater net lumen gain in the analysis segment (0.68 [0.60] vs 1.0 [0.61] mm; P<.001) due to stenting and no edge restenosis. Conclusion Sirolimus-eluting stents result in superior clinical and angiographic outcomes compared with vascular brachytherapy for the treatment of restenosis within a bare-metal stent. [ABSTRACT FROM AUTHOR]

KMN-159 is the lead compound from a series of novel difluorolactam prostanoid EP 4 receptor agonists aimed at inducing local bone formation while avoiding the inherent side effects of systemic EP 4 activation. KMN-159 is a potent, selective small molecule possessing pharmacokinetic properties amenable to local administration. Unfractionated rat bone marrow cells (BMCs) were treated once at plating with escalating doses of KMN-159 (1 pM to 10 μM). The resulting elevated alkaline phosphatase (ALP) levels measured 9 days post-dose are consistent with increased osteoblastic differentiation and exposure to KMN-159 at low nanomolar concentrations for as little as 30 min was sufficient to induce complete osteoblast differentiation of the BMCs from both sexes and regardless of age. ALP induction was blocked by an EP 4 receptor antagonist but not by EP 1 or EP 2 receptor antagonists and was not induced by EP 2 or EP 3 receptor agonists. Addition of BMCs to plates coated with KMN-159 24 days earlier resulted in ALP activation, highlighting the chemical stability of the compound. The expression of phenotype markers such as ALP, type I collagen, and osteocalcin was significantly elevated throughout the osteoblastic differentiation timecourse initiated by KMN-159 stimulation. An increased number of tartrate-resistant acid phosphatase-positive cells was observed KMN-159 or PGE 2 treated BMCs but only in the presence of exogenous receptor activator of nuclear factor kappa-Β ligand (RANKL). No change in the number of adipocytes was observed. KMN-159 also increased bone healing in a rat calvarial defect model with a healing rate equivalent to recombinant human bone morphogenetic protein-2. Our studies show that KMN-159 is able to stimulate osteoblastic differentiation with a very short time of exposure, supporting its potential as a therapeutic candidate for augmenting bone mass. [ABSTRACT FROM AUTHOR]