Cannabidiol (CBD) is ubiquitous in state-based medical cannabis programs and consumer products for complementary health or recreational use. CBD has intrinsic pharmacologic effects and associated ...adverse drug events (ADEs) along with the potential for pharmacokinetic and pharmacodynamic drug-drug interactions (DDIs). Given CBD use among patients with complex conditions and treatment regimens, as well as its expanded consumer use, awareness of potential safety issues with CBD is needed. Prescribing information for federally approved products containing CBD were reviewed. Data on ADEs and DDIs were extracted and summarized. Nearly one-half of CBD users experienced ADEs, which displayed a general dose-response relationship. Common ADEs include transaminase elevations, sedation, sleep disturbances, infection, and anemia. Given CBD effects on common biological targets implicated in drug metabolism (e.g., CYP3A4/2C19) and excretion (e.g., P-glycoprotein), the potential for DDIs with commonly used medication is high. General clinical recommendations of reducing substrate doses, monitoring for ADEs, and finding alternative therapy should be considered, especially in medically complex patients. CBD is implicated as both a victim and perpetrator of DDIs and has its own ADE profile. These effects should be considered in the risk-benefit assessment of CBD therapy and patients and consumers made aware of potential safety issues with CBD use.
After several decades, therapeutic cancer vaccines now show signs of efficacy and potential to help patients resistant to other standard-of-care immunotherapies, but they have yet to realize their ...full potential and expand the oncologic armamentarium. Here, we classify cancer vaccines by what is known of the included antigens, which tumors express those antigens and where the antigens colocalize with antigen-presenting cells, thus delineating predefined vaccines (shared or personalized) and anonymous vaccines (ex vivo or in situ). To expedite clinical development, we highlight the need for accurate immune monitoring of early trials to acknowledge failures and advance the most promising vaccines.
Tetrahydrocannabinol (THC) is the primary psychoactive ingredient in cannabis. While the safety of THC and cannabis has been extrapolated from millennia of recreational use, medical marijuana ...programs have increased exposure among medically complex individuals with comorbid conditions and many co-prescribed medications. Thus, THC should be recognized as a pharmacologically complex compound with potential for drug-drug interactions and adverse drug events. This review summarizes potential adverse drug events related to THC when combined with other medications. Metabolic drug-drug interactions are primarily due to THC conversion by CYP3A4 and CYP2C9, which can be impacted by several common medications. Further, CYP2C9 polymorphisms are highly prevalent in certain racial groups (up to 35% in Caucasians) and increase the bioavailability of THC. THC also has broad interactions with drug-metabolizing enzymes and can enhance adverse effects of other medications. Pharmacodynamic interactions include neurological effects, impact on the cardiovascular system, and risk of infection. General clinical recommendations for THC use include starting with low doses and titrating to desired effects. However, many interactions may be unavoidable, dose-limiting, or a barrier to THC-based therapy. Future work and research must establish sufficient data resources to capture medical marijuana use for such studies. Meanwhile, clinicians should balance the potential risks of THC and cannabis and the lack of strong evidence of efficacy in many conditions with patient desires for alternative therapy.
We present new constraints on the star formation histories of six ultra-faint dwarf galaxies: Bootes I, Canes Venatici II, Coma Berenices, Hercules, Leo IV, and Ursa Major I. Our analysis employs a ...combination of high-precision photometry obtained with the Advanced Camera for Surveys on the Hubble Space Telescope, medium-resolution spectroscopy obtained with the DEep Imaging Multi-Object Spectrograph on the W. M. Keck Observatory, and updated Victoria-Regina isochrones tailored to the abundance patterns appropriate for these galaxies. The data for five of these Milky Way satellites are best fit by a star formation history where at least 75% of the stars formed by z ~ 10 (13.3 Gyr ago). All of the galaxies are consistent with 80% of the stars forming by z ~ 6 (12.8 Gyr ago) and 100% of the stars forming by z ~ 3 (11.6 Gyr ago). The similarly ancient populations of these galaxies support the hypothesis that star formation in the smallest dark-matter sub-halos was suppressed by a global outside influence, such as the reionization of the universe.
Neoplasms change over time through a process of cell-level evolution, driven by genetic and epigenetic alterations. However, the ecology of the microenvironment of a neoplastic cell determines which ...changes provide adaptive benefits. There is widespread recognition of the importance of these evolutionary and ecological processes in cancer, but to date, no system has been proposed for drawing clinically relevant distinctions between how different tumours are evolving. On the basis of a consensus conference of experts in the fields of cancer evolution and cancer ecology, we propose a framework for classifying tumours that is based on four relevant components. These are the diversity of neoplastic cells (intratumoural heterogeneity) and changes over time in that diversity, which make up an evolutionary index (Evo-index), as well as the hazards to neoplastic cell survival and the resources available to neoplastic cells, which make up an ecological index (Eco-index). We review evidence demonstrating the importance of each of these factors and describe multiple methods that can be used to measure them. Development of this classification system holds promise for enabling clinicians to personalize optimal interventions based on the evolvability of the patient's tumour. The Evo- and Eco-indices provide a common lexicon for communicating about how neoplasms change in response to interventions, with potential implications for clinical trials, personalized medicine and basic cancer research.
Indolent non-Hodgkin's lymphomas (iNHLs) are incurable with standard therapy and are poorly responsive to checkpoint blockade. Although lymphoma cells are efficiently killed by primed T cells, in ...vivo priming of anti-lymphoma T cells has been elusive. Here, we demonstrate that lymphoma cells can directly prime T cells, but in vivo immunity still requires cross-presentation. To address this, we developed an in situ vaccine (ISV), combining Flt3L, radiotherapy, and a TLR3 agonist, which recruited, antigen-loaded and activated intratumoral, cross-presenting dendritic cells (DCs). ISV induced anti-tumor CD8
T cell responses and systemic (abscopal) cancer remission in patients with advanced stage iNHL in an ongoing trial ( NCT01976585 ). Non-responding patients developed a population of PD1
CD8
T cells after ISV, and murine tumors became newly responsive to PD1 blockade, prompting a follow-up trial of the combined therapy. Our data substantiate that recruiting and activating intratumoral, cross-priming DCs is achievable and critical to anti-tumor T cell responses and PD1-blockade efficacy.
The risk of community-acquired pneumonia (CAP) increases with age and significantly impacts morbidity and mortality in the elderly population. The burden of illness and cost of preventing CAP has not ...been compared to other serious diseases.
This retrospective analysis used claims data from 2014 to 2015 and compared hospitalizations for CAP, myocardial infarction (MI), stroke, and osteoporotic fractures (OF) in adults aged ≥65 years enrolled in a Medicare Advantage insurance plan. Individuals who had not already been hospitalized for one of these conditions and did not have evidence of long-term care were included in the study. Hospitalizations for each condition were described by length of stay, readmissions, mortality, and total costs. Preventive measures included vaccinations for CAP and medications for MI, stroke, and OF.
A total of 1,949,352 individuals were included in the cohort. In 2015, the rate of CAP-related hospitalizations was the highest at 846.7 per 100,000 person-years compared to 405 for MI, 278.9 for stroke, and 343.9 for OF. Vaccination costs for CAP were $40.2 million including $14.1 million for pneumococcal and $26.1 million for influenza vaccines. The cost of preventive medications for MI and stroke reached over $661 million and OF totaled $169 million.
Although CAP has a higher burden of hospitalization and total costs than MI, stroke, and OF in the elderly population, prevention efforts were disproportionately smaller for CAP. Prioritization of CAP prevention is needed to substantially reduce the burden of CAP.
Abstract
Using deep observations obtained with the Advanced Camera for Surveys (ACS) on board the
Hubble Space Telescope (HST)
, we demonstrate that the sub-solar stellar initial mass function (IMF) ...of six ultra-faint dwarf Milky Way satellites (UFDs) is more bottom light than the IMF of the Milky Way disk. Our data have a lower-mass limit of ∼0.45
M
⊙
, while the upper limit is ∼0.8
M
⊙
, set by the turnoff mass of these old, metal-poor systems. If formulated as a single power law, we obtain a shallower IMF slope than the Salpeter value of −2.3, ranging from −1.01 for Leo IV to −1.87 for Boötes I. The significance of these deviations depends on the galaxy and is typically 95% or more. When modeled as a log-normal, the IMF fit results in a higher peak mass than in the Milky Way disk, but a Milky Way disk value for the characteristic system mass (∼0.22
M
⊙
) is excluded at only 68% significance, and only for some UFDs in the sample. We find that the IMF slope correlates well with the galaxy mean metallicity, and to a lesser degree, with the velocity dispersion and the total mass. The strength of the observed correlations is limited by shot noise in the number of observed stars, but future space-based missions like the
James Webb Space Telescope
(JWST
) and the
Wide-Field Infrared Survey Telescope (
WFIRST)
will enhance both the number of dwarf Milky Way satellites that can be studied in such detail and the observation depth for individual galaxies.
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