Recent advances in pyridine synthesis are described. Modification of traditional condensation strategies continues to be a recurrent theme in contemporary literature. Advancements in ...transition‐metal‐catalyzed cyclization and cross‐coupling procedures offer new routes to functionalized pyridine derivatives. These recently developed methodologies are a valuable addition to azaheterocycle synthesis.
Closing the ring: Modification of traditional condensation strategies continues to be a recurrent theme in contemporary literature. Advancements in transition‐metal‐catalyzed cyclization and cross‐coupling procedures offer new routes to functionalized pyridine derivatives (see scheme).
The results of large clinical trials have led physicians and patients to question the safety of hormone therapy for menopause. In the past, physicians prescribed hormone therapy to improve overall ...health and prevent cardiac disease, as well as for symptoms of menopause. Combined estrogen/progestogen therapy, but not estrogen alone, increases the risk of breast cancer when used for more than three to five years. Therefore, in women with a uterus, it is recommended that physicians prescribe combination therapy only to treat menopausal symptoms such as vasomotor symptoms (hot flashes) and vaginal atrophy, using the smallest effective dosage for the shortest possible duration. Although estrogen is the most effective treatment for hot flashes, nonhormonal alternatives such as low-dose paroxetine, venlafaxine, and gabapentin are effective alternatives. Women with a uterus who are using estrogen should also take a progestogen to reduce the risk of endometrial cancer. Women who cannot tolerate adverse effects of progestogens may benefit from a combined formulation of estrogen and the selective estrogen receptor modulator bazedoxifene. There is no highquality, consistent evidence that yoga, paced respiration, acupuncture, exercise, stress reduction, relaxation therapy, and alternative therapies such as black cohosh, botanical products, omega-3 fatty acid supplements, and dietary Chinese herbs benefit patients more than placebo. One systematic review suggests modest improvement in hot flashes and vaginal dryness with soy products, and small studies suggest that clinical hypnosis significantly reduces hot flashes. Patients with genitourinary syndrome of menopause may benefit from vaginal estrogen, nonhormonal vaginal moisturizers, or ospemifene (the only nonhormonal treatment approved by the U.S. Food and Drug Administration for dyspareunia due to menopausal atrophy). The decision to use hormone therapy depends on clinical presentation, a thorough evaluation of the risks and benefits, and an informed discussion with the patient.
The current outbreak of Zika virus (ZIKV) infection has been associated with an apparent increased risk of congenital microcephaly. We describe a case of a pregnant woman and her fetus infected with ...ZIKV during the 11th gestational week. The fetal head circumference decreased from the 47th percentile to the 24th percentile between 16 and 20 weeks of gestation. ZIKV RNA was identified in maternal serum at 16 and 21 weeks of gestation. At 19 and 20 weeks of gestation, substantial brain abnormalities were detected on ultrasonography and magnetic resonance imaging (MRI) without the presence of microcephaly or intracranial calcifications. On postmortem analysis of the fetal brain, diffuse cerebral cortical thinning, high ZIKV RNA loads, and viral particles were detected, and ZIKV was subsequently isolated.
The Paris Agreement's goal of limiting the increase in global temperature to 1.5° or 2°C above preindustrial levels requires rapid reductions in greenhouse gas emissions. Although reducing emissions ...from fossil fuels is essential for meeting this goal, other sources of emissions may also preclude its attainment. We show that even if fossil fuel emissions were immediately halted, current trends in global food systems would prevent the achievement of the 1.5°C target and, by the end of the century, threaten the achievement of the 2°C target. Meeting the 1.5°C target requires rapid and ambitious changes to food systems as well as to all nonfood sectors. The 2°C target could be achieved with less-ambitious changes to food systems, but only if fossil fuel and other nonfood emissions are eliminated soon.
Significance Our assessment of the life cycle air quality impacts on human health of 10 alternatives to conventional gasoline vehicles finds that electric vehicles (EVs) powered by electricity from ...natural gas or wind, water, or solar power are best for improving air quality, whereas vehicles powered by corn ethanol and EVs powered by coal are the worst. This work advances the current debate over the environmental impacts of conventional versus alternative transportation options by combining detailed spatially and temporally explicit emissions inventories with state-of-the-science air quality impact analysis using advanced chemical transport modeling. Our results reinforce previous findings that air quality-related health damages from transportation are generally comparable to or larger than climate change-related damages.
Commonly considered strategies for reducing the environmental impact of light-duty transportation include using alternative fuels and improving vehicle fuel economy. We evaluate the air quality-related human health impacts of 10 such options, including the use of liquid biofuels, diesel, and compressed natural gas (CNG) in internal combustion engines; the use of electricity from a range of conventional and renewable sources to power electric vehicles (EVs); and the use of hybrid EV technology. Our approach combines spatially, temporally, and chemically detailed life cycle emission inventories; comprehensive, fine-scale state-of-the-science chemical transport modeling; and exposure, concentration–response, and economic health impact modeling for ozone (O ₃) and fine particulate matter (PM ₂.₅). We find that powering vehicles with corn ethanol or with coal-based or “grid average” electricity increases monetized environmental health impacts by 80% or more relative to using conventional gasoline. Conversely, EVs powered by low-emitting electricity from natural gas, wind, water, or solar power reduce environmental health impacts by 50% or more. Consideration of potential climate change impacts alongside the human health outcomes described here further reinforces the environmental preferability of EVs powered by low-emitting electricity relative to gasoline vehicles.
Mechanistic air pollution modeling is essential in air quality management, yet the extensive expertise and computational resources required to run most models prevent their use in many situations ...where their results would be useful. Here, we present InMAP (Intervention Model for Air Pollution), which offers an alternative to comprehensive air quality models for estimating the air pollution health impacts of emission reductions and other potential interventions. InMAP estimates annual-average changes in primary and secondary fine particle (PM2.5) concentrations-the air pollution outcome generally causing the largest monetized health damages-attributable to annual changes in precursor emissions. InMAP leverages pre-processed physical and chemical information from the output of a state-of-the-science chemical transport model and a variable spatial resolution computational grid to perform simulations that are several orders of magnitude less computationally intensive than comprehensive model simulations. In comparisons run here, InMAP recreates comprehensive model predictions of changes in total PM2.5 concentrations with population-weighted mean fractional bias (MFB) of -17% and population-weighted R2 = 0.90. Although InMAP is not specifically designed to reproduce total observed concentrations, it is able to do so within published air quality model performance criteria for total PM2.5. Potential uses of InMAP include studying exposure, health, and environmental justice impacts of potential shifts in emissions for annual-average PM2.5. InMAP can be trained to run for any spatial and temporal domain given the availability of appropriate simulation output from a comprehensive model. The InMAP model source code and input data are freely available online under an open-source license.
Poorly differentiated thyroid carcinomas (PDTC) in young individuals are rare and their clinical and histopathologic features, genetic mechanisms, and outcomes remain largely unknown. Here, we report ...a detailed characterization of a series of six PDTC in patients ≤21 years old defined by Turin diagnostic criteria studied for mutations and gene fusions characteristic of thyroid cancer using targeted next-generation sequencing (NGS) and whole-exome sequencing (WES). All tumors had solid, insular, or trabecular growth pattern and high mitotic rate, and five out of six tumors showed tumor necrosis. Targeted NGS assay identified somatic mutations in the DICER1 gene in five of six (83%) tumors, all of which were "hotspot" mutations encoding the metal-ion binding sites of the RNase IIIb domain of DICER1. WES was performed in five cases which confirmed all hotspot mutations and detected two tumors with additional inactivating DICER1 alterations. Of these two, one was a germline pathogenic DICER1 variant and the other had loss of heterozygosity for DICER1. No other mutations or gene fusions characteristic of adult well-differentiated thyroid cancer and PDTC (BRAF, RAS, TERT, RET/PTC, and other) were detected. On follow-up, available for five patients, three patients died of disease 8-24 months after diagnosis, whereas two were alive with no disease. The results of our study demonstrate that childhood- and adolescent-onset PDTC are genetically distinct from adult-onset PDTC in that they are strongly associated with DICER1 mutations and may herald DICER1 syndrome in a minority. As such, all young persons with PDTC may benefit from genetic counseling. Furthermore, their clinically aggressive behavior contrasts sharply with the indolent nature of the great majority of thyroid tumors with DICER1 mutations reported to date.
The role of fluorine in drug design and development is expanding rapidly as we learn more about the unique properties associated with this unusual element and how to deploy it with greater ...sophistication. The judicious introduction of fluorine into a molecule can productively influence conformation, pK a, intrinsic potency, membrane permeability, metabolic pathways, and pharmacokinetic properties. In addition, 18F has been established as a useful positron emitting isotope for use with in vivo imaging technology that potentially has extensive application in drug discovery and development, often limited only by convenient synthetic accessibility to labeled compounds. The wide ranging applications of fluorine in drug design are providing a strong stimulus for the development of new synthetic methodologies that allow more facile access to a wide range of fluorinated compounds. In this review, we provide an update on the effects of the strategic incorporation of fluorine in drug molecules and applications in positron emission tomography.
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