Neuroprotective efficacy of P7C3 compounds in primate hippocampus.

There is a critical need for translating basic science discoveries into new therapeutics for patients suffering from difficult to treat neuropsychiatric and neurodegenerative conditions. Previously, a target-agnostic in vivo screen in mice identified P7C3 aminopropyl carbazole as capable of enhancing the net magnitude of postnatal neurogenesis by protecting young neurons from death. Subsequently, neuroprotective efficacy of P7C3 compounds in a broad spectrum of preclinical rodent models has also been observed. An important next step in translating this work to patients is to determine whether P7C3 compounds exhibit similar efficacy in primates. Adult male rhesus monkeys received daily oral P7C3-A20 or vehicle for 38 weeks. During weeks 2-11, monkeys received weekly injection of 5'-bromo-2-deoxyuridine (BrdU) to label newborn cells, the majority of which would normally die over the following 27 weeks. BrdU+ cells were quantified using unbiased stereology. Separately in mice, the proneurogenic efficacy of P7C3-A20 was compared to that of NSI-189, a proneurogenic drug currently in clinical trials for patients with major depression. Orally-administered P7C3-A20 provided sustained plasma exposure, was well-tolerated, and elevated the survival of hippocampal BrdU+ cells in nonhuman primates without adverse central or peripheral tissue effects. In mice, NSI-189 was shown to be pro-proliferative, and P7C3-A20 elevated the net magnitude of hippocampal neurogenesis to a greater degree than NSI-189 through its distinct mechanism of promoting neuronal survival. This pilot study provides evidence that P7C3-A20 safely protects neurons in nonhuman primates, suggesting that the neuroprotective efficacy of P7C3 compounds is likely to translate to humans as well

The impact of time and team on primary cytoreduction outcomes

The degree of cytoreduction at time of initial surgery for epithelial ovarian cancers is correlated with overall survival. Given that surgery can be physically and mentally taxing on the surgeon, we sought to examine if there were temporal and/or team relationships related to primary cytoreduction outcomes

Competing Conservation Objectives for Predators and Prey: Estimating Killer Whale Prey Requirements for Chinook Salmon

Ecosystem-based management (EBM) of marine resources attempts to conserve interacting species. In contrast to single-species fisheries management, EBM aims to identify and resolve conflicting objectives for different species. Such a conflict may be emerging in the northeastern Pacific for southern resident killer whales (Orcinus orca) and their primary prey, Chinook salmon (Oncorhynchus tshawytscha). Both species have at-risk conservation status and transboundary (Canada–US) ranges. We modeled individual killer whale prey requirements from feeding and growth records of captive killer whales and morphometric data from historic live-capture fishery and whaling records worldwide. The models, combined with caloric value of salmon, and demographic and diet data for wild killer whales, allow us to predict salmon quantities needed to maintain and recover this killer whale population, which numbered 87 individuals in 2009. Our analyses provide new information on cost of lactation and new parameter estimates for other killer whale populations globally. Prey requirements of southern resident killer whales are difficult to reconcile with fisheries and conservation objectives for Chinook salmon, because the number of fish required is large relative to annual returns and fishery catches. For instance, a U.S. recovery goal (2.3% annual population growth of killer whales over 28 years) implies a 75% increase in energetic requirements. Reducing salmon fisheries may serve as a temporary mitigation measure to allow time for management actions to improve salmon productivity to take effect. As ecosystem-based fishery management becomes more prevalent, trade-offs between conservation objectives for predators and prey will become increasingly necessary. Our approach offers scenarios to compare relative influence of various sources of uncertainty on the resulting consumption estimates to prioritise future research efforts, and a general approach for assessing the extent of conflict between conservation objectives for threatened or protected wildlife where the interaction between affected species can be quantified

Dust in Comet C/2007 N3 (Lulin)

We report optical imaging, optical and near-infrared polarimetry, and Spitzer mid-infrared spectroscopy of comet C/2007 N3 (Lulin). Polarimetric observations were obtained in R (0.676 micron) at phase angles from 0.44 degrees to 21 degrees with simultaneous observations in H (1.65 micron) at 4.0 degrees, exploring the negative branch in polarization. Comet C/2007 N3 (Lulin) shows typical negative polarization in the optical as well as a similar negative branch near-infrared wavelengths. The 10 micron silicate feature is only weakly in emission and according to our thermal models, is consistent with emission from a mixture of silicate and carbon material. We argue that large, low-porosity (akin to Ballistic Particle Cluster Aggregates) rather absorbing aggregate dust particles best explain both the polarimetric and the mid-infrared spectral energy distribution.Comment: 18 pages, 9 figures, 3 table

Prevalence and Course of Depression During the First Year After Mild to Moderate Stroke

Background: This study examined the prevalence and longitudinal course of depression during the first year after mild to moderate stroke. Methods and Results: We identified patients with mild to moderate ischemic stroke or intracerebral hemorrhage (National Institutes of Health Stroke Scale score <16) and at least 1 depression assessment at 3, 6, or 12 months after stroke (n=648, 542, and 533, respectively) from the Brain Attack Surveillance in Corpus Christi project (2014–2016). Latent transition analysis was used to examine temporal profiles of depressive symptoms assessed by the 8‐item Patient Health Questionnaire between 3 and 12 months after stroke. Mean age was 65.6 years, 49.4% were women, and 56.7% were Mexican Americans. The prevalence of depression after stroke was 35.3% at 3 months, decreased to 24.9% at 6 months, and remained stable at 25.7% at 12 months. Approximately half of the participants classified as having depression at 3 or 6 months showed clinical improvement at the next assessment. Subgroups with distinct patterns of depressive symptoms were identified, including mild/no symptoms, predominant sleep disturbance and fatigue symptoms, affective symptoms, and severe/all symptoms. A majority of participants with mild/no symptoms retained this symptom pattern over time. The probability of transitioning to mild/no symptoms was higher before 6 months compared with the later period, and severe symptoms were more likely to persist after 6 months compared with the earlier period. Conclusions: The observed dynamics of depressive symptoms suggest that depression after stroke tends to persist after 6 months among patients with mild to moderate stroke and should be continually monitored and appropriately managed

Common Reasons That Asymptomatic Patients Who Are 65 Years and Older Receive Carotid Imaging

IMPORTANCE: National guidelines do not agree on the role of carotid screening in asymptomatic patients (ie, patients who have not had a stroke or transient ischemic attack). Recently, several physician organizations participating in the Choosing Wisely campaign have identified carotid imaging in selected asymptomatic populations as being of low value. However, the majority of patients who are evaluated for carotid stenosis and subsequently revascularized are asymptomatic. OBJECTIVE: To better understand why asymptomatic patients who undergo revascularization receive initial carotid imaging. DESIGN, SETTING, AND PARTICIPANTS: Retrospective cohort study of 4127 Veterans Health Administration patients 65 years and older undergoing carotid revascularization for asymptomatic carotid stenosis between 2005 and 2009. MAIN OUTCOMES AND MEASURES: Indications for carotid ultrasounds were extracted using trained abstractors. Frequency of indications and appropriateness of initial carotid ultrasound imaging for patients within each rating category after the intervention were reported. RESULTS: The mean (SD) age of this cohort of 4127 patients was 73.6 (5.9) years; 4014 (98.8%) were male. Overall, there were 5226 indications for 4063 carotid ultrasounds. The most common indications listed were carotid bruit (1578 [30.2% of indications]) and follow-up for carotid disease (stenosis/history of carotid disease) in patients who had previously documented carotid stenosis (1087 [20.8% of indications]). Multiple vascular risk factors were the next most common indication listed. Rates of appropriate, uncertain, and inappropriate imaging were 5.4% (227 indications), 83.4% (3387 indications), and 11.3% (458 indications), respectively. Among the most common inappropriate indications were dizziness/vertigo and syncope. Among the 4063 patients, 3373 (83.0%) received a carotid endarterectomy. Overall, 663 procedures were performed in patients 80 years and older. CONCLUSIONS AND RELEVANCE: Carotid bruit and follow-up for carotid disease accounted for approximately half of all indications provided by physicians for carotid testing. Strong consideration should be given to improving the evidence base around carotid testing, especially around monitoring stenosis over long periods and evaluating carotid bruits. Targeting carotid ultrasound ordering with decision support tools may also be an important step in reducing use of low-value imaging

Well-being at a Military Medical School and Implications for Military Retention.

INTRODUCTION: Physical and psychological well-being play a critical role in the academic and professional development of medical students and can alter the trajectory of a student\u27s quality of personal and professional life. Military medical students, given their dual role as officer and student, experience unique stressors and issues that may play a role in their future intentions to continue military service, as well as practice medicine. As such, this study explores well-being across the 4 years of medical school at Uniformed Services University (USU) and how well-being relates to a student\u27s likelihood to continue serving in the military and practicing medicine. METHODS: In September 2019, 678 USU medical students were invited to complete a survey consisting of three sections-the Medical Student Well-being Index (MSWBI), a single-item burnout measure, and six questions regarding their likelihood of staying in the military and medical practice. Survey responses were analyzed using descriptive statistics, analysis of variance (ANOVA), and contingency table analysis. Additionally, thematic analysis was conducted on open-ended responses included as part of the likelihood questions. RESULTS: Our MSWBI and burnout scores suggest that the overall state of well-being among medical students at USU is comparable to other studies of the medical student population. ANOVA revealed class differences among the four cohorts, highlighted by improved well-being scores as students transitioned from clerkships to their fourth-year curriculum. Fewer clinical students (MS3s and MS4s), compared to pre-clerkship students, indicated a desire to stay in the military. In contrast, a higher percentage of clinical students seemed to reconsider their medical career choice compared to their pre-clerkship student counterparts. Medicine-oriented likelihood questions were associated with four unique MSWBI items, whereas military-oriented likelihood questions were associated with one unique MSWBI item. CONCLUSION: The present study found that the overall state of well-being in USU medical students is satisfactory, but opportunities for improvement exist. Medical student well-being seemed to have a stronger association with medicine-oriented likelihood items than with military-oriented likelihood items. To obtain and refine best practices for strengthening engagement and commitment, future research should examine if and how military and medical contexts converge and diverge throughout training. This may enhance the medical school and training experience and, ultimately, reinforce, or strengthen, the desire and commitment to practice and serve in military medicine

Roles of Hormone Replacement Therapy and Menopause on Osteoarthritis and Cardiovascular Disease Outcomes: A Narrative Review

Osteoarthritis (OA) is a highly prevalent condition characterized by degradation of the joints. OA and cardiovascular disease (CVD) are leading contributors to disease burden worldwide, with a high level of overlap between the risk factors and occurrence of both conditions. Chief among the risk factors that contribute to OA and CVD are sex and age, which are both independent and interacting traits. Specifically, the prevalence of both conditions is higher in older women, which may be mediated by the occurrence of menopause. Menopause represents a significant transition in a women's life, and the rapid decline in circulating sex hormones, estrogen and progesterone, leads to complex physiological changes. Declines in hormone levels may partially explain the increase in prevalence of OA and CVD in post-menopausal women. In theory, the use of hormone therapy (HT) may buffer adverse effects of menopause; however, it is unclear whether HT offers protective effects for the onset or progression of these diseases. Studies have shown mixed results when describing the influence of HT on disease risk among post-menopausal women, which warrants further exploration. The roles that increasing age, female sex, HT, and CVD play in OA risk demonstrate that OA is a multifaceted condition. This review provides a timely consolidation of current literature and suggests aims for future research directions to bridge gaps in the understanding of how OA, CVD, and HT interact in post-menopausal women

Discovery of an intermediate-luminosity red transient in M51 and its likely dust-obscured, infrared-variable progenitor

We present the discovery of an optical transient (OT) in Messier 51, designated M51 OT2019-1 (also ZTF19aadyppr, AT 2019abn, ATLAS19bzl), by the Zwicky Transient Facility (ZTF). The OT rose over 15 days to an observed luminosity of $M_r=-13$ (${\nu}L_{\nu}=9\times10^6~L_{\odot}$), in the luminosity gap between novae and typical supernovae (SNe). Spectra during the outburst show a red continuum, Balmer emission with a velocity width of $\approx400$ km s$^{-1}$, Ca II and [Ca II] emission, and absorption features characteristic of an F-type supergiant. The spectra and multiband light curves are similar to the so-called "SN impostors" and intermediate-luminosity red transients (ILRTs). We directly identify the likely progenitor in archival Spitzer Space Telescope imaging with a $4.5~\mu$m luminosity of $M_{[4.5]}\approx-12.2$ and a $[3.6]-[4.5]$ color redder than 0.74 mag, similar to those of the prototype ILRTs SN 2008S and NGC 300 OT2008-1. Intensive monitoring of M51 with Spitzer further reveals evidence for variability of the progenitor candidate at [4.5] in the years before the OT. The progenitor is not detected in pre-outburst Hubble Space Telescope optical and near-IR images. The optical colors during outburst combined with spectroscopic temperature constraints imply a higher reddening of $E(B-V)\approx0.7$ mag and higher intrinsic luminosity of $M_r\approx-14.9$ (${\nu}L_{\nu}=5.3\times10^7~L_{\odot}$) near peak than seen in previous ILRT candidates. Moreover, the extinction estimate is higher on the rise than on the plateau, suggestive of an extended phase of circumstellar dust destruction. These results, enabled by the early discovery of M51 OT2019-1 and extensive pre-outburst archival coverage, offer new clues about the debated origins of ILRTs and may challenge the hypothesis that they arise from the electron-capture induced collapse of extreme asymptotic giant branch stars.Comment: 21 pages, 5 figures, published in ApJ