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    Why?. Some are afraid the devices make them look old. Others refuse to believe they have a hearing problem. Others don’t believe they will improve their ability to hear because of an experience a friend or family member shared.

    Sound familiar?. Maybe it’s time to familiarize yourself with a few FAQs about hearing aids. What is a hearing aid?. A hearing aid is a small electronic device worn behind the ear or in the ear canal.

    It amplifies sound so that a person with hearing loss can hear sound better. Hearing devices have three components. A microphone, amplifier and speaker. Sound comes through the microphone and is converted into an electrical signal and sent to the amplifier.

    The amplifier increases the power of the signals and sends them to the ear through the speaker. Today’s hearing aid is much smaller and more powerful than the hearing devices our parents and grandparents wore even 10 years ago. Advances in digital technology make them better able to distinguish conversation in noisy environments. Many are Bluetooth capable and connect with smartphones and other personal electronic devices we now use on a daily basis.

    More. See the different types and styles of hearing aids Can hearing aids improve my hearing?. That depends on what type of hearing loss you have. Sensorineural hearing loss is caused by damage to the sensory hair cells of the inner ear.

    This damage can be caused by exposure to loud noise, illness, medication, injury or age. If your hearing healthcare professional determines you have sensorineural hearing loss, you will probably benefit from wearing a hearing aid. Age-related hearing loss, generally a subset of sensorineural, is the loss of hearing that occurs in most people as they age. This condition, known medically as presbycusis, is common and can often be improved with hearing aids.

    Conductive hearing loss, however is usually caused by an obstruction in the ear canal, such as swelling due to an ear infection or a benign tumor. If your hearing healthcare professional determines your hearing loss is conductive, your hearing may return to normal once the obstruction has been removed. If your hearing does not return to normal, you may benefit from wearing a hearing aid, cochlear implant or bone-anchored hearing system. What should I look for when choosing a hearing aid?.

    That depends on your lifestyle and your budget. An active person who enjoys traveling and athletic activities will most likely need a different model of hearing aid than someone who spends most of their time at home watching television. Your hearing healthcare professional will ask a variety of questions to help you determine what type of amplification you need, then work with you to make sure your hearing device works properly to help you hear the sounds that are most important to you. Remember that friend who told you they keep their hearing aids in the dresser drawer?.

    That just might be because they weren’t honest with their hearing healthcare professional about their expectations and lifestyle, or didn’t schedule follow-up visits as requested. How long will it take for me to adjust to wearing hearing aids?. Wondering what to expect from new hearing aids?. Adjusting to hearing aids varies from person to person and depends upon how long you waited to treat your hearing loss as well as its severity.

    Although our ears collect noise from our environment, it’s actually our brain that translates it into recognizable sound. If hearing loss is left untreated, the auditory part of your brain can actually atrophy, in which case your rehabilitation may take a while longer. You’ll also want to wear them as recommended. Following your doctor’s orders improves your chances for success.

    More. 7 tips for getting used to hearing aids How long do hearing aids last?. With proper use and maintenance, hearing aids typically last between three and five years. Can I return my hearing aids if I’m not satisfied?.

    Many hearing centers offer a trial period to ensure you are satisfied. Be sure to ask your hearing healthcare professional about their policies before you purchase any hearing device. How can I find out if I need a hearing aid?. The best way to find out if you need a hearing aid is to have your hearing tested by a hearing healthcare professional.

    A thorough hearing test will take approximately an hour of your time during which you will most likely be asked to provide your health history, undergo a series of hearing assessments, and discuss your lifestyle and expectations for better hearing. Afterward, a hearing healthcare professional will discuss the results of your test with you and, if its determined that your hearing can benefit from amplification, discuss next steps. If your hearing has changed recently or you suspect you have hearing loss, make an appointment to see a hearing healthcare professional in your community as soon as possible. There’s a lot to hear in this world – laughing children, music, the sound of someone you love calling your name – and hearing aids may be able to help you hear them.When deciding on a new pair of hearing aids, you should consider how long they will last.

    Just like buying a car, the actual mileage may vary.Most modern high-quality hearing aids have a life expectancy on average between three and seven years. However, keep in mind that two people can buy exactly the same hearing aids and have them last vastly different amounts of time. Here's why. New hearing aids generally last aroundfive years, but this depends on a lotof different factors.

    Factors impacting how long hearing aids will last There are at least nine factors that impact the average lifespan of a hearing aid. Materials used to make hearing aids Frequency of cleaning Where hearing aids are worn How hearing aids are stored Hearing aid style A person's body physiology Frequency of maintenance Technological advancements Unique hearing needs 1. Materials used to make hearing aids Although they are designed to be durable, hearing aids are made of plastic, metal, silicon, polymers and other materials that may be subject to some degree of structural degradation over time. Most hearing aids sold today have a protective nanocoating on them to resist water, dust and moisture, but you should still treat them gently to protect them from shock and impacts.

    2. Frequency of cleaning Most people would never dream of going months without washing their hair, face or body. However, they forget their hearing aids are exposed to the same environment—moisture, dust, skin oils and sweat, extreme temperatures and sunlight. All this occurs in addition to the earwax generated by your ear canal in its natural cleaning process.

    Some wearers only have their hearing aids professionally cleaned twice a year or so. This takes a toll on hearing aids and can significantly reduce their life expectancy. To help your hearing aids life expectancy, clean them daily as directed by your hearing care practitioner and have them professionally cleaned in the hearing clinic every three to four months. 3.

    Where hearing aids are worn Hearing aids that are consistently in damp or dusty environments often have more performance issues than other hearing aids. If you’re concerned about the environments in which you wear your hearing aids, consult your hearing care professional for ideas about protective measures. You may need to use protective sleeves or schedule more frequent professional cleanings to extend the life of your hearing aids. 4.

    How hearing aids are stored The way hearing aids are stored when you’re not wearing them can also be a factor in hearing aid life expectancy. For hearing aids with disposable batteries, storing hearing aids with the battery door open will keep them safer. A case with a dehumidifier will keep them drier as well, which will also help them last longer. Ask your hearing care practitioner what type of storage case or dehumidifier options would work best for your hearing aids.

    For rechargeable hearing aids, lithium batteries last about four to five years. Just like with smartphones, the battery lifespan gets shorter the longer you own the device. If you notice your battery draining faster than usual, speak to your hearing care provider about whether new rechargeable batteries will help, or if you should get new devices. 5.

    Style of hearing aids Conventional wisdom in the hearing aid industry is that behind-the-ear (BTE) styles tend to have a long lifespan than in-the-ear (ITE) styles. The reason behind this wisdom is more of the electronic components sit in the damp environment of the ear canal with ITE styles. However, recent technical advancements in nanocoatings on internal and external components may soon make this durability difference a thing of the past. 6.

    Your body’s physiology Some body chemistries are harder on the plastic and metal components of hearing aids and tend to discolor or degrade parts much faster than others. Some people have very oily skin, produce a lot of earwax or sweat profusely–all of these factors can impact hearing aid life, too. You can’t control these things, of course, but if you have any of these issues you should discuss them with your hearing care practitioner when you’re selecting hearing aids. 7.

    Frequency of maintenance Most hearing aids have some readily-replaceable parts, such as wax guards, earmold tubing and silicone dome earpiece tips. These parts are regularly replaced during routine maintenance visits with your hearing care practitioner. There are other parts which can usually be replaced or repaired in the clinic if they become damaged or nonfunctional, like battery doors, earmolds, external speakers and microphone covers. These types of maintenance activities are very important for making your hearing aids last as long as possible.

    8. Technological advancements Hearing aid technology changes often.Many new hearing aids can connectto phones via Bluetooth, for example. Obsolescence can become an issue for very old hearing aids. After several years (usually between five and 10), hearing aid manufacturers may stop making replacement parts for a particular aid, which may make repairs on old hearing aids difficult or impossible.

    Software used to program hearing aids also changes over time and eventually becomes obsolete. This often makes it difficult to reprogram very old hearing aids. Hearing aid performance and features advance very rapidly. The technology in the most advanced hearing aids available six or seven years ago would be considered basic today.

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    Dewsnap C, buy generic prozac online no prescription Sauer prozac for bipolar U, Evans C. Sex Transm Infect 2020;96:79. Doi. 10.1136/sextrans-2019-054397This article was previously published with missing information.

    Please note the below:The authors would like to acknowledge their gratitude to Daniel Richardson, Zara Haider, Ceri Evans, Janet Michaelis and Elizabeth Foley for providing a helpful format for this piece.Richardson D, Haider Z, Evans C, et al. The joint BASHH-FSRH conference. Sex Transm Infect 2017;93:380. Doi.

    10.1136/sextrans-2017-053184Using cytokine expression to distinguish between active and treated syphilis. Promising but not yet ready for prime timeDistinguishing between previously treated and active syphilis can be challenging in the subset of treated patients with serofast status, defined as persistent non-treponemal seropositivity (<4-fold decline in rapid plasma reagin titre ≥6 months after treatment). The study investigated whether serum cytokine expression levels, measured with a 62-cytokine multiplex bead-based ELISA, can help guide clinical management. Using samples from patients with active, treated and serofast syphilis, the authors developed a two-cytokine (brain-derived neurotrophic factor and tumour necrosis factor β) decision tree that showed good accuracy (82%) and sensitivity (100%) but moderate specificity (45%).

    While further studies will be needed to confirm and refine the diagnostic algorithm, there also remain important technical, operational and financial barriers to implementing such cytokine assays in routine care.Kojima N, Siebert JC, Maecker H, et al. The application of cytokine expression assays to differentiate active from previously treated syphilis. J Infect Dis. 2020 [published online ahead of print, 2020 Mar 19].Global and regional prevalence of herpes simplex virus type 2 infection.

    Updated estimates for people aged 15–49 yearsEstimates of genital herpes simplex virus (HSV) infections across regions inform advocacy and resource planning and guide the development of improved control measures, including vaccines. In 2016, HSV-2 affected 13% of the global population aged 15–49 years (high-risk groups excluded), totalling 491 million people. Of note, by excluding people aged >49 years, the analysis knowingly underestimated the true burden of HSV-2 infection.1 Prevalence showed a slight increase relative to 2012 and was highest in Africa and Americas and among women. Given the association between HSV-2 and subsequent HIV infection,2 it is concerning that HSV-2 was estimated to affect ~50% of women aged 25–34 years in the African region.

    The analysis also estimated the prevalence of genital HSV-1 (3%), but uncertainty intervals were wide.James C, Harfouche M, Welton NJ, et al. Herpes simplex virus. Global infection prevalence and incidence estimates, 2016. Bull World Health Organ.

    2020. 98. 315-329.Observed pregnancy and neonatal outcomes in women with HIV exposed to recommended antiretroviral regimensThis large Italian observational cohort study analysed data from 794 pregnant women who were exposed within 32 weeks of gestation to recommended antiretroviral regimens in the period 2008–2018. Treatment comprised three-drug combinations of an nucleoside reverse transcriptase inhibitor (NRTI) backbone plus a ritonavir-boosted protease inhibitor (78%, predominantly atazanavir), an non-NRTI (NNRTI) (15%, predominantly nevirapine) or an integrase strand transfer inhibitor (INSTI.

    6%, predominantly raltegravir). No major differences were found for a wide range of pregnancy and neonatal outcomes, including major congenital defects. The rate of HIV transmission ranged up to 2.4% in this study. This comprehensive evaluation will be useful for clinicians caring for women with HIV.

    More outcome data are needed for regimens comprising second-generation INSTIs.Floridia M, Dalzero S, Giacomet V, et al. Pregnancy and neonatal outcomes in women with HIV-1 exposed to integrase inhibitors, protease inhibitors and non-nucleoside reverse transcriptase inhibitors. An observational study. Infection 2020;48:249–258.HIV status and sexual practice independently correlate with gut dysbiosis and unique microbiota signaturesGut dysbiosis may contribute to persistent inflammation in people with HIV (PWH) who receive antiretroviral therapy (ART).

    The study compared the gut microbiota of ART-treated PWH and HIV-negative controls matched for age, gender, country of birth, body mass index and sexual practice. Regardless of sex and sexual practice, the gut microbiota differed significantly in PWH vrsus controls, with expansion of proinflammatory gut bacteria and depletion of homeostasis-promoting microbiota members. The extent of dysbiosis correlated with serum inflammatory markers, nadir and pre-ART CD4 cell counts, and prevalence of non-infectious comorbidities. Further studies are warranted to elucidate causality and investigate microbiota-mediated strategies to alleviate HIV-associated inflammation.

    Independent of HIV status, and in both men and women, receptive anal intercourse was associated with a unique microbiota signature.Vujkovic-Cvijin I, Sortino O, Verheij E, et al. HIV-associated gut dysbiosis is independent of sexual practice and correlates with non-communicable diseases. Nat Commun. 2020;11:2448.Reducing the cost of molecular STI screening in resource-limited settings.

    An optimised sample-pooling algorithmInfections with Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG) are frequently asymptomatic and, if untreated, may lead to severe reproductive complications in women. Molecular testing is highly sensitive but costly, especially for resource-limited settings. This modelling study explored a sample pooling strategy for CT and NG testing among women in Zambia. Based on cross-sectional data, participants were stratified into high, intermediate and low prevalence groups, and the respective specimens were mathematically modelled to be tested individually, in pools of 3, or pools of 4, using the GeneXpert instrument.

    Overall, the pooling strategy was found to maintain acceptable sensitivity (ranging from 80% to 100%), while significantly lowering cost per sample. Investigation in additional cohorts will validate whether the approach may increase access to STI screening where resourced are constrained.Connolly S, Kilembe W, Inambao M, et al. A population-specific optimized GeneXpert pooling algorithm for Chlamydia trachomatis and Neisseria gonorrhoeae to reduce cost of molecular STI screening in resource-limited settings. J Clin Microbiol.

    2020 [published online ahead of print, 2020 Jun 10].Girl-only HPV vaccination can eliminate cervical cancer in most low and lower middle income countries by the end of the century, but must be supplemented by screening in high incidence countriesProgress towards the global elimination of cervical cancer must include effective interventions in lower-middle income countries (LMICs). The study modelled the effect over the next century of girls-only human papilloma virus (HPV) vaccination with or without once-lifetime or twice-lifetime cervical screening in 78 LMICs, assuming 90% vaccine coverage, 100% lifetime protection and screening uptake increasing from 45% (2023) to 90% (2045 onwards). Vaccination alone would substantially reduce cancer incidence (61 million cases averted) and achieve elimination (<5 cases per 100 000 women-years) in 60% of LMICs. However, high-incidence countries, predominantly in Africa, might not reach elimination by vaccination alone.

    Adding twice-lifetime screening would achieve elimination of cervical cancer in 100% of LMICs. Results have informed the targets of 90% HPV vaccination coverage, 70% screening coverage and 90% of cervical lesions treated by 2030 recently announced by the WHO.Brisson M, Kim JJ, Canfell K, et al. Impact of HPV vaccination and cervical screening on cervical cancer elimination. A comparative modelling analysis in 78 low-income and lower-middle-income countries.

    Dewsnap C, buy prozac fluoxetine online Sauer U, Evans C. Sex Transm Infect 2020;96:79. Doi. 10.1136/sextrans-2019-054397This article was previously published with missing information. Please note the below:The authors would like to acknowledge their gratitude to Daniel Richardson, Zara Haider, Ceri Evans, Janet Michaelis and Elizabeth Foley for providing a helpful format for this piece.Richardson D, Haider Z, Evans C, et al.

    The joint BASHH-FSRH conference. Sex Transm Infect 2017;93:380. Doi. 10.1136/sextrans-2017-053184Using cytokine expression to distinguish between active and treated syphilis. Promising but not yet ready for prime timeDistinguishing between previously treated and active syphilis can be challenging in the subset of treated patients with serofast status, defined as persistent non-treponemal seropositivity (<4-fold decline in rapid plasma reagin titre ≥6 months after treatment).

    The study investigated whether serum cytokine expression levels, measured with a 62-cytokine multiplex bead-based ELISA, can help guide clinical management. Using samples from patients with active, treated and serofast syphilis, the authors developed a two-cytokine (brain-derived neurotrophic factor and tumour necrosis factor β) decision tree that showed good accuracy (82%) and sensitivity (100%) but moderate specificity (45%). While further studies will be needed to confirm and refine the diagnostic algorithm, there also remain important technical, operational and financial barriers to implementing such cytokine assays in routine care.Kojima N, Siebert JC, Maecker H, et al. The application of cytokine expression assays to differentiate active from previously treated syphilis. J Infect Dis.

    2020 [published online ahead of print, 2020 Mar 19].Global and regional prevalence of herpes simplex virus type 2 infection. Updated estimates for people aged 15–49 yearsEstimates of genital herpes simplex virus (HSV) infections across regions inform advocacy and resource planning and guide the development of improved control measures, including vaccines. In 2016, HSV-2 affected 13% of the global population aged 15–49 years (high-risk groups excluded), totalling 491 million people. Of note, by excluding people aged >49 years, the analysis knowingly underestimated the true burden of HSV-2 infection.1 Prevalence showed a slight increase relative to 2012 and was highest in Africa and Americas and among women. Given the association between HSV-2 and subsequent HIV infection,2 it is concerning that HSV-2 was estimated to affect ~50% of women aged 25–34 years in the African region.

    The analysis also estimated the prevalence of genital HSV-1 (3%), but uncertainty intervals were wide.James C, Harfouche M, Welton NJ, et al. Herpes simplex virus. Global infection prevalence and incidence estimates, 2016. Bull World Health Organ. 2020.

    98. 315-329.Observed pregnancy and neonatal outcomes in women with HIV exposed to recommended antiretroviral regimensThis large Italian observational cohort study analysed data from 794 pregnant women who were exposed within 32 weeks of gestation to recommended antiretroviral regimens in the period 2008–2018. Treatment comprised three-drug combinations of an nucleoside reverse transcriptase inhibitor (NRTI) backbone plus a ritonavir-boosted protease inhibitor (78%, predominantly atazanavir), an non-NRTI (NNRTI) (15%, predominantly nevirapine) or an integrase strand transfer inhibitor (INSTI. 6%, predominantly raltegravir). No major differences were found for a wide range of pregnancy and neonatal outcomes, including major congenital defects.

    The rate of HIV transmission ranged up to 2.4% in this study. This comprehensive evaluation will be useful for clinicians caring for women with HIV. More outcome data are needed for regimens comprising second-generation INSTIs.Floridia M, Dalzero S, Giacomet V, et al. Pregnancy and neonatal outcomes in women with HIV-1 exposed to integrase inhibitors, protease inhibitors and non-nucleoside reverse transcriptase inhibitors. An observational study.

    Infection 2020;48:249–258.HIV status and sexual practice independently correlate with gut dysbiosis and unique microbiota signaturesGut dysbiosis may contribute to persistent inflammation in people with HIV (PWH) who receive antiretroviral therapy (ART). The study compared the gut microbiota of ART-treated PWH and HIV-negative controls matched for age, gender, country of birth, body mass index and sexual practice. Regardless of sex and sexual practice, the gut microbiota differed significantly in PWH vrsus controls, with expansion of proinflammatory gut bacteria and depletion of homeostasis-promoting microbiota members. The extent of dysbiosis correlated with serum inflammatory markers, nadir and pre-ART CD4 cell counts, and prevalence of non-infectious comorbidities. Further studies are warranted to elucidate causality and investigate microbiota-mediated strategies to alleviate HIV-associated inflammation.

    Independent of HIV status, and in both men and women, receptive anal intercourse was associated with a unique microbiota signature.Vujkovic-Cvijin I, Sortino O, Verheij E, et al. HIV-associated gut dysbiosis is independent of sexual practice and correlates with non-communicable diseases. Nat Commun. 2020;11:2448.Reducing the cost of molecular STI screening in resource-limited settings. An optimised sample-pooling algorithmInfections with Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG) are frequently asymptomatic and, if untreated, may lead to severe reproductive complications in women.

    Molecular testing is highly sensitive but costly, especially for resource-limited settings. This modelling study explored a sample pooling strategy for CT and NG testing among women in Zambia. Based on cross-sectional data, participants were stratified into high, intermediate and low prevalence groups, and the respective specimens were mathematically modelled to be tested individually, in pools of 3, or pools of 4, using the GeneXpert instrument. Overall, the pooling strategy was found to maintain acceptable sensitivity (ranging from 80% to 100%), while significantly lowering cost per sample. Investigation in additional cohorts will validate whether the approach may increase access to STI screening where resourced are constrained.Connolly S, Kilembe W, Inambao M, et al.

    A population-specific optimized GeneXpert pooling algorithm for Chlamydia trachomatis and Neisseria gonorrhoeae to reduce cost of molecular STI screening in resource-limited settings. J Clin Microbiol. 2020 [published online ahead of print, 2020 Jun 10].Girl-only HPV vaccination can eliminate cervical cancer in most low and lower middle income countries by the end of the century, but must be supplemented by screening in high incidence countriesProgress towards the global elimination of cervical cancer must include effective interventions in lower-middle income countries (LMICs). The study modelled the effect over the next century of girls-only human papilloma virus (HPV) vaccination with or without once-lifetime or twice-lifetime cervical screening in 78 LMICs, assuming 90% vaccine coverage, 100% lifetime protection and screening uptake increasing from 45% (2023) to 90% (2045 onwards). Vaccination alone would substantially reduce cancer incidence (61 million cases averted) and achieve elimination (<5 cases per 100 000 women-years) in 60% of LMICs.

    However, high-incidence countries, predominantly in Africa, might not reach elimination by vaccination alone. Adding twice-lifetime screening would achieve elimination of cervical cancer in 100% of LMICs. Results have informed the targets of 90% HPV vaccination coverage, 70% screening coverage and 90% of cervical lesions treated by 2030 recently announced by the WHO.Brisson M, Kim JJ, Canfell K, et al. Impact of HPV vaccination and cervical screening on cervical cancer elimination. A comparative modelling analysis in 78 low-income and lower-middle-income countries.

    Can prozac cause weight loss

    Johns Hopkins can prozac cause weight loss researchers say that Get More Info a drug approved to treat lung cancer substantially slowed the growth of tumors, in mice, caused by a rare form of bone cancer. Reporting in the journal PLOS ONE, the researchers say the finding offers hope to chordoma patients, who have no treatment options once surgery and radiation have been exhausted. There are can prozac cause weight loss no U.S. Food and Drug Administration-approved medications for the disease and, because its incidence is only one in 1 million, there is little financial incentive for pharmaceutical companies to develop or test drugs to treat them.

    €œThe encouraging news is that this drug is already used in humans to treat lung cancer,” says study leader can prozac cause weight loss Gary L. Gallia, M.D., Ph.D., an assistant professor of neurosurgery and oncology at the Johns Hopkins University School of Medicine. Chordoma occurs at the base of the skull and in the bones of the spine. This cancer is thought to arise from remnants of the cartilage-like structure that serves can prozac cause weight loss as a scaffold for the formation of the spinal column.

    These so-called notochord cells normally persist after birth and are lodged inside the spine and skull. In rare cases, they become malignant tumors can prozac cause weight loss. The tumors are generally slow-growing but tend to recur, and their proximity to critical structures such as the spinal cord, cranial nerves and brain stem make them difficult to treat. Median survival time is seven years after diagnosis.

    Since chordoma is so rare, few models have existed to even study it outside cells in a petri dish, can prozac cause weight loss says Gallia, who together with colleagues last year developed a mouse model of the disorder. The model was created by implanting human tumor tissue into a mouse. The researchers can prozac cause weight loss began their drug studies by first examining the makeup of the tumor cells in their mouse model to determine what might be causing the cells to grow and divide uncontrolled. They saw that the epidermal growth factor receptor (EGFR) pathway was active and suspected that it played a critical role in the malignancy.

    Gallia and his colleagues tested two FDA-approved drugs known to inhibit EGFR and found that erlotinib was able to better slow the growth of chordoma than gefitinib. They then tested erlotinib can prozac cause weight loss in mice transplanted with human chordoma tumors. After 37 days of treatment, the average tumor volume in the control group was more than three times larger than in those animals that were treated with erlotinib. Further research can prozac cause weight loss indicated that EGFR activation was significantly reduced.

    €œWe hit our target,” Gallia says. €œIt drastically reduced the growth of the tumors.” Gallia says he hopes his findings will lead to testing in chordoma patients. Although a controlled clinical trial would be ideal, can prozac cause weight loss he says it may be difficult to get funding to test treatments for such a rare disease. Alternatively, he says he hopes erlotinib might be used in selected patients whose tumors are shown to have active EGFRs and who have run out of other treatment options.

    This research was can prozac cause weight loss supported by the Chordoma Foundation as well as Dr. And Mrs. Irving J. Sherman.

    Other Johns Hopkins researchers involved in the study include I-Mei Siu, Ph.D.. Jacob Ruzevick. Qi Zhao, Ph.D.. Nick Connis.

    Yuchen Jiao, Ph.D.. Chetan Bettegowda, M.D., Ph.D.. Xuewei Xia, M.D.. Peter C.

    Burger, M.D.. And Christine L. Hann, M.D., Ph.D. For more information about Gallia, click here, and click here for more information about chordoma care at Johns Hopkins.Using cervical fluid obtained during routine Pap tests, scientists at the Johns Hopkins Kimmel Cancer Center have developed a test to detect ovarian and endometrial cancers.

    In a pilot study, the “PapGene” test, which relies on genomic sequencing of cancer-specific mutations, accurately detected all 24 (100 percent) endometrial cancers and nine of 22 (41 percent) ovarian cancers. Results of the experiments are published in the Jan. 9 issue of the journal Science Translational Medicine. The investigators note that larger-scale studies are needed before clinical implementation can begin, but they believe the test has the potential to pioneer genomic-based cancer screening tests.

    The Papanicolaou (Pap) test, during which cells collected from the cervix are examined for microscopic signs of cancer, is widely and successfully used to screen for cervical cancers. However, no routine screening method is available for ovarian or endometrial cancers. Since the Pap test occasionally contains cells shed from the ovaries or endometrium, cancer cells arising from these organs could be present in the fluid as well, says Luis Diaz, M.D., associate professor of oncology at Johns Hopkins, as well as director of translational medicine at the Ludwig Center for Cancer Genetics and Therapeutics and director of the Swim Across America Laboratory, also at Johns Hopkins. The laboratory is sponsored by a volunteer organization that raises funds for cancer research through swim events.

    €œOur genomic sequencing approach may offer the potential to detect these cancer cells in a scalable and cost-effective way,” adds Diaz. Hear Diaz discuss the research in this podcast, courtesy of the American Association for the Advancement of Science, and watch an animation describing the PapGene test. Cervical fluid of patients with gynecologic cancer carries normal cellular DNA mixed together with DNA from cancer cells, according to the investigators. The investigators’ task was to use genomic sequencing to distinguish cancerous from normal DNA.

    The scientists had to determine the most common genetic changes in ovarian and endometrial cancers in order to prioritize which genomic regions to include in their test. They searched publicly available genome-wide studies of ovarian cancer, including those done by other Johns Hopkins investigators, to find mutations specific to ovarian cancer. Such genome-wide studies were not available for the most common type of endometrial cancer, so they conducted genome-wide sequencing studies on 22 of these endometrial cancers. From the ovarian and endometrial cancer genome data, the Johns Hopkins-led team identified 12 of the most frequently mutated genes in both cancers and developed the PapGene test with this insight in mind.

    The investigators then applied PapGene on Pap test samples from ovarian and endometrial cancer patients at The Johns Hopkins Hospital, Memorial Sloan-Kettering Cancer Center, the University of São Paulo in Brazil and ILSbio, a tissue bank. The new test detected both early- and late-stage disease in the endometrial and ovarian cancers tested. No healthy women in the control group were misclassified as having cancer. The investigators’ next steps include applying PapGene on more samples and working to increase the test’s sensitivity in detecting ovarian cancer.

    €œPerforming the test at different times during the menstrual cycle, inserting the cervical brush deeper into the cervical canal, and assessing more regions of the genome may boost the sensitivity,” says Chetan Bettegowda, M.D., Ph.D., assistant professor of neurosurgery at Johns Hopkins and a member of the Ludwig Center as well. Together, ovarian and endometrial cancers are diagnosed in nearly 70,000 women in the United States each year, and about one-third of them will die from it. €œGenomic-based tests could help detect ovarian and endometrial cancers early enough to cure more of them,” says graduate student Yuxuan Wang, who notes that the cost of the test could be similar to current cervical fluid HPV testing, which is less than $100. PapGene is a high-sensitivity approach for the detection of cancer-specific DNA mutations, according to the investigators.

    However, false mutations can be erroneously created during the many steps — including amplification, sequencing and analysis — required to prepare the DNA collected from a Pap test specimen for sequencing. This required the investigators to build a safeguard into PapGene’s sequencing method, designed to weed out artifacts that could lead to misleading test results. €œIf unaccounted for, artifacts could lead to a false positive test result and incorrectly indicate that a healthy person has cancer,” says graduate student Isaac Kinde. Kinde added a unique genetic barcode — a random set of 14 DNA base pairs — to each DNA fragment at an initial stage of the sample preparation process.

    Although each DNA fragment is copied many times before eventually being sequenced, all of the newly copied DNA can be traced back to one original DNA molecule through their genetic barcodes. If the copies originating from the same DNA molecule do not all contain the same mutation, then an artifact is suspected and the mutation is disregarded. However, bonafide mutations, which exist in the sample before the initial barcoding step, will be present in all of the copies originating from the original DNA molecule. Funding for the research was provided by Swim Across America, the Commonwealth Fund, the Hilton-Ludwig Cancer Prevention Initiative, the Virginia &.

    D.K. Ludwig Fund for Cancer Research, the Experimental Therapeutics Center of the Memorial Sloan-Kettering Cancer Center, the Chia Family Foundation, The Honorable Tina Brozman Foundation, the United Negro College Fund/Merck Graduate Science Research Dissertation Fellowship, the Burroughs Wellcome Career Award for Medical Scientists, the National Colorectal Cancer Research Alliance and the National Institutes of Health’s National Cancer Institute (N01-CN-43309, CA129825, CA43460). In addition to Kinde, Bettegowda, Wang and Diaz, investigators participating in the research include Jian Wu, Nishant Agrawal, Ie-Ming Shih, Robert Kurman, Robert Giuntoli, Richard Roden and James R. Eshleman from Johns Hopkins.

    Nickolas Papadopoulos, Kenneth Kinzler and Bert Vogelstein from the Ludwig Center at Johns Hopkins. Fanny Dao and Douglas A. Levine from Memorial Sloan-Kettering Cancer Center. And Jesus Paula Carvalho and Suely Kazue Nagahashi Marie from the University of São Paulo.

    Papadopoulos, Kinzler, Vogelstein and Diaz are co-founders of Inostics and Personal Genome Diagnostics. They own stocks in the companies and are members of their Scientific Advisory Boards. Inostics and Personal Genome Diagnostics have licensed several patent applications from Johns Hopkins. These relationships are subject to certain restrictions under The Johns Hopkins University policy, and the terms of these arrangements are managed by the university in accordance with its conflict-of-interest policies..

    Johns Hopkins researchers say that a drug approved to treat lung cancer substantially slowed the growth of tumors, in mice, caused by a rare form of bone buy prozac fluoxetine online cancer. Reporting in the journal PLOS ONE, the researchers say the finding offers hope to chordoma patients, who have no treatment options once surgery and radiation have been exhausted. There are buy prozac fluoxetine online no U.S. Food and Drug Administration-approved medications for the disease and, because its incidence is only one in 1 million, there is little financial incentive for pharmaceutical companies to develop or test drugs to treat them. €œThe encouraging news buy prozac fluoxetine online is that this drug is already used in humans to treat lung cancer,” says study leader Gary L.

    Gallia, M.D., Ph.D., an assistant professor of neurosurgery and oncology at the Johns Hopkins University School of Medicine. Chordoma occurs at the base of the skull and in the bones of the spine. This cancer is buy prozac fluoxetine online thought to arise from remnants of the cartilage-like structure that serves as a scaffold for the formation of the spinal column. These so-called notochord cells normally persist after birth and are lodged inside the spine and skull. In rare buy prozac fluoxetine online cases, they become malignant tumors.

    The tumors are generally slow-growing but tend to recur, and their proximity to critical structures such as the spinal cord, cranial nerves and brain stem make them difficult to treat. Median survival time is seven years after diagnosis. Since chordoma is so rare, few models have existed to even study it outside cells in a petri dish, says Gallia, who together with colleagues buy prozac fluoxetine online last year developed a mouse model of the disorder. The model was created by implanting human tumor tissue into a mouse. The researchers began their drug studies by buy prozac fluoxetine online first examining the makeup of the tumor cells in their mouse model to determine what might be causing the cells to grow and divide uncontrolled.

    They saw that the epidermal growth factor receptor (EGFR) pathway was active and suspected that it played a critical role in the malignancy. Gallia and his colleagues tested two FDA-approved drugs known to inhibit EGFR and found that erlotinib was able to better slow the growth of chordoma than gefitinib. They then tested erlotinib buy prozac fluoxetine online in mice transplanted with human chordoma tumors. After 37 days of treatment, the average tumor volume in the control group was more than three times larger than in those animals that were treated with erlotinib. Further research indicated that EGFR activation was buy prozac fluoxetine online significantly reduced.

    €œWe hit our target,” Gallia says. €œIt drastically reduced the growth of the tumors.” Gallia says he hopes his findings will lead to testing in chordoma patients. Although a controlled clinical trial would be ideal, he says it may be difficult to get funding to test treatments for such a rare buy prozac fluoxetine online disease. Alternatively, he says he hopes erlotinib might be used in selected patients whose tumors are shown to have active EGFRs and who have run out of other treatment options. This research buy prozac fluoxetine online was supported by the Chordoma Foundation as well as Dr.

    And Mrs. Irving J. Sherman. Other Johns Hopkins researchers involved in the study include I-Mei Siu, Ph.D.. Jacob Ruzevick.

    Qi Zhao, Ph.D.. Nick Connis. Yuchen Jiao, Ph.D.. Chetan Bettegowda, M.D., Ph.D.. Xuewei Xia, M.D..

    Peter C. Burger, M.D.. And Christine L. Hann, M.D., Ph.D. For more information about Gallia, click here, and click here for more information about chordoma care at Johns Hopkins.Using cervical fluid obtained during routine Pap tests, scientists at the Johns Hopkins Kimmel Cancer Center have developed a test to detect ovarian and endometrial cancers.

    In a pilot study, the “PapGene” test, which relies on genomic sequencing of cancer-specific mutations, accurately detected all 24 (100 percent) endometrial cancers and nine of 22 (41 percent) ovarian cancers. Results of the experiments are published in the Jan. 9 issue of the journal Science Translational Medicine. The investigators note that larger-scale studies are needed before clinical implementation can begin, but they believe the test has the potential to pioneer genomic-based cancer screening tests. The Papanicolaou (Pap) test, during which cells collected from the cervix are examined for microscopic signs of cancer, is widely and successfully used to screen for cervical cancers.

    However, no routine screening method is available for ovarian or endometrial cancers. Since the Pap test occasionally contains cells shed from the ovaries or endometrium, cancer cells arising from these organs could be present in the fluid as well, says Luis Diaz, M.D., associate professor of oncology at Johns Hopkins, as well as director of translational medicine at the Ludwig Center for Cancer Genetics and Therapeutics and director of the Swim Across America Laboratory, also at Johns Hopkins. The laboratory is sponsored by a volunteer organization that raises funds for cancer research through swim events. €œOur genomic sequencing approach may offer the potential to detect these cancer cells in a scalable and cost-effective way,” adds Diaz. Hear Diaz discuss the research in this podcast, courtesy of the American Association for the Advancement of Science, and watch an animation describing the PapGene test.

    Cervical fluid of patients with gynecologic cancer carries normal cellular DNA mixed together with DNA from cancer cells, according to the investigators. The investigators’ task was to use genomic sequencing to distinguish cancerous from normal DNA. The scientists had to determine the most common genetic changes in ovarian and endometrial cancers in order to prioritize which genomic regions to include in their test. They searched publicly available genome-wide studies of ovarian cancer, including those done by other Johns Hopkins investigators, to find mutations specific to ovarian cancer. Such genome-wide studies were not available for the most common type of endometrial cancer, so they conducted genome-wide sequencing studies on 22 of these endometrial cancers.

    From the ovarian and endometrial cancer genome data, the Johns Hopkins-led team identified 12 of the most frequently mutated genes in both cancers and developed the PapGene test with this insight in mind. The investigators then applied PapGene on Pap test samples from ovarian and endometrial cancer patients at The Johns Hopkins Hospital, Memorial Sloan-Kettering Cancer Center, the University of São Paulo in Brazil and ILSbio, a tissue bank. The new test detected both early- and late-stage disease in the endometrial and ovarian cancers tested. No healthy women in the control group were misclassified as having cancer. The investigators’ next steps include applying PapGene on more samples and working to increase the test’s sensitivity in detecting ovarian cancer.

    €œPerforming the test at different times during the menstrual cycle, inserting the cervical brush deeper into the cervical canal, and assessing more regions of the genome may boost the sensitivity,” says Chetan Bettegowda, M.D., Ph.D., assistant professor of neurosurgery at Johns Hopkins and a member of the Ludwig Center as well. Together, ovarian and endometrial cancers are diagnosed in nearly 70,000 women in the United States each year, and about one-third of them will die from it. €œGenomic-based tests could help detect ovarian and endometrial cancers early enough to cure more of them,” says graduate student Yuxuan Wang, who notes that the cost of the test could be similar to current cervical fluid HPV testing, which is less than $100. PapGene is a high-sensitivity approach for the detection of cancer-specific DNA mutations, according to the investigators. However, false mutations can be erroneously created during the many steps — including amplification, sequencing and analysis — required to prepare the DNA collected from a Pap test specimen for sequencing.

    This required the investigators to build a safeguard into PapGene’s sequencing method, designed to weed out artifacts that could lead to misleading test results. €œIf unaccounted for, artifacts could lead to a false positive test result and incorrectly indicate that a healthy person has cancer,” says graduate student Isaac Kinde. Kinde added a unique genetic barcode — a random set of 14 DNA base pairs — to each DNA fragment at an initial stage of the sample preparation process. Although each DNA fragment is copied many times before eventually being sequenced, all of the newly copied DNA can be traced back to one original DNA molecule through their genetic barcodes. If the copies originating from the same DNA molecule do not all contain the same mutation, then an artifact is suspected and the mutation is disregarded.

    However, bonafide mutations, which exist in the sample before the initial barcoding step, will be present in all of the copies originating from the original DNA molecule. Funding for the research was provided by Swim Across America, the Commonwealth Fund, the Hilton-Ludwig Cancer Prevention Initiative, the Virginia &. D.K. Ludwig Fund for Cancer Research, the Experimental Therapeutics Center of the Memorial Sloan-Kettering Cancer Center, the Chia Family Foundation, The Honorable Tina Brozman Foundation, the United Negro College Fund/Merck Graduate Science Research Dissertation Fellowship, the Burroughs Wellcome Career Award for Medical Scientists, the National Colorectal Cancer Research Alliance and the National Institutes of Health’s National Cancer Institute (N01-CN-43309, CA129825, CA43460). In addition to Kinde, Bettegowda, Wang and Diaz, investigators participating in the research include Jian Wu, Nishant Agrawal, Ie-Ming Shih, Robert Kurman, Robert Giuntoli, Richard Roden and James R.

    Eshleman from Johns Hopkins. Nickolas Papadopoulos, Kenneth Kinzler and Bert Vogelstein from the Ludwig Center at Johns Hopkins. Fanny Dao and Douglas A. Levine from Memorial Sloan-Kettering Cancer Center. And Jesus Paula Carvalho and Suely Kazue Nagahashi Marie from the University of São Paulo.

    Papadopoulos, Kinzler, Vogelstein and Diaz are co-founders of Inostics and Personal Genome Diagnostics. They own stocks in the companies and are members of their Scientific Advisory Boards. Inostics and Personal Genome Diagnostics have licensed several patent applications from Johns Hopkins. These relationships are subject to certain restrictions under The Johns Hopkins University policy, and the terms of these arrangements are managed by the university in accordance with its conflict-of-interest policies..

    I took prozac while pregnant

    While there’s been plenty of grim news to come out effects of prozac during pregnancy of the COVID-19 pandemic, there have also been a i took prozac while pregnant few heartwarming trends, too. For one, since March animal shelters throughout the U.S. Have seen i took prozac while pregnant a significant spike in animal adoptions and foster care placements — particularly for dogs. As people settled into quarantine, shelters across the country began reporting an unprecedented amount of requests by people wanting to adopt dogs. In addition, Kitty Block, CEO and president of the Humane Society of the United States, says that in March and April the number of nationwide foster animal placements increased by 40 to 50 percent from 2019.

    During one week in March alone, placements soared by 790 percent compared to the same time period last i took prozac while pregnant year. This boom in adoptions and foster placements stems from an obvious cause. For people stuck at home, the idea i took prozac while pregnant of animal companionship is now more appealing than ever. And studies from experts in human-animal interaction have shown that dogs can have a measurably positive effect on your mental health.     Pets for Stress Relief Even limited interaction with dogs and other animals can have a beneficial impact on humans. Last year, Patricia Pendry, a human development researcher at Washington State University, led a study that tested college animal visitation programs, where domesticated animals are brought on campus during exam weeks to provide stress relief for students.

    Researchers divided 249 participants into four groups, who were i took prozac while pregnant then given 10 minutes to interact with dogs and cats to varying degrees. One group was allowed to pet the animals, another watched dogs receive pets and a third was simply shown images. The participants’ saliva was tested for cortisol, a stress i took prozac while pregnant hormone, before and after. The researchers found that cortisol levels significantly decreased among students who directly pet dogs during that 10-minute interval.   Pendry says that her study did not differentiate how dogs impacted stress relief compared to cats, so it’s unclear if dogs decrease cortisol levels more effectively than their feline friends. She suspects that depends on a person’s personal preference, but notes that the stress relief benefits of dog-human interactions tend to be more visible due to the animal’s energetic behavior.  “Dogs tend to be animals who very actively seek out interaction with people,” says Pendry.

    “They make i took prozac while pregnant eye contact. They enjoy being pet. They evoke in people i took prozac while pregnant that feeling that it’s all about them. They just seem completely thrilled to interact with the individual and people end up feeling very loved and attended to and special. That's very appealing.” Trauma Therapy Spending time with dogs can also help those struggling with serious mental health issues such as post-traumatic stress disorder.

    In a study published in March, Florida Atlantic University nursing researcher Cheryl Krause-Parello and her colleagues looked at how walking with shelter dogs impacted veterans suffering i took prozac while pregnant from PTSD. Over the course of four weeks, 33 veterans took part in weekly 30-minute dog walks. The scientists measured psychological and physiological stress indicators, like cortisol levels and heart rate variability, among the participants both before and after the strolls i took prozac while pregnant. A control group walked with another human instead of a dog.     The study found that walking with dogs tended to decrease signs of PTSD — particularly variability in heart rate — in veterans with severe symptoms more than walking with another human. Krause-Parello says that the study is preliminary, but it does suggest animals can help relieve the effects of PTSD.

    Plus, that animal i took prozac while pregnant companionship can have measurable benefits for veterans. She adds that the study was set up so veterans could adopt a shelter job and have their adoption fee covered. Afterwards, several of them choose to do so.            “We had the veterans pick the dog’s names out of the hat,” says Krause-Parello, who also directs Canines Providing Assistance to Wounded Warriors, a research initiative that i took prozac while pregnant examines how dogs influence the health and well-being of veterans. “We didn’t want anyone to get too attached to one of the animals in case they got adopted. But one of them picked a name out of the hat, walked the dog, and immediately came back and put in an application to adopt that dog.

    That was really fun.” Pendry notes that it’s important to consider how these interactions impact both the human and the animal. Animal-human interplay can be mutually beneficial, helping improve the health and well-being of the animal while also providing mental health benefits for the human.   “When we’re studying marital functioning, for example, you wouldn’t just ask one spouse, you ideally take both perspectives,” Pendry says. “That’s the same with human-animal interactions — we have to consider the well-being and functioning of the animal, because there’s a lot to be gained for them, as well.”       .

    While there’s been buy prozac fluoxetine online plenty of grim news to come out of the COVID-19 pandemic, there have also been a few heartwarming trends, too. For one, since March animal shelters throughout the U.S. Have seen a significant spike in animal adoptions and foster care placements buy prozac fluoxetine online — particularly for dogs. As people settled into quarantine, shelters across the country began reporting an unprecedented amount of requests by people wanting to adopt dogs.

    In addition, Kitty Block, CEO and president of the Humane Society of the United States, says that in March and April the number of nationwide foster animal placements increased by 40 to 50 percent from 2019. During one week in March alone, placements soared by 790 percent compared to the same time period last year buy prozac fluoxetine online. This boom in adoptions and foster placements stems from an obvious cause. For people buy prozac fluoxetine online stuck at home, the idea of animal companionship is now more appealing than ever.

    And studies from experts in human-animal interaction have shown that dogs can have a measurably positive effect on your mental health.     Pets for Stress Relief Even limited interaction with dogs and other animals can have a beneficial impact on humans. Last year, Patricia Pendry, a human development researcher at Washington State University, led a study that tested college animal visitation programs, where domesticated animals are brought on campus during exam weeks to provide stress relief for students. Researchers divided 249 participants into four groups, who were then given 10 minutes to interact with dogs and cats to varying degrees buy prozac fluoxetine online. One group was allowed to pet the animals, another watched dogs receive pets and a third was simply shown images.

    The participants’ saliva was tested for cortisol, a stress hormone, before and buy prozac fluoxetine online after. The researchers found that cortisol levels significantly decreased among students who directly pet dogs during that 10-minute interval.   Pendry says that her study did not differentiate how dogs impacted stress relief compared to cats, so it’s unclear if dogs decrease cortisol levels more effectively than their feline friends. She suspects that depends on a person’s personal preference, but notes that the stress relief benefits of dog-human interactions tend to be more visible due to the animal’s energetic behavior.  “Dogs tend to be animals who very actively seek out interaction with people,” says Pendry. “They make eye buy prozac fluoxetine online contact.

    They enjoy being pet. They evoke in buy prozac fluoxetine online people that feeling that it’s all about them. They just seem completely thrilled to interact with the individual and people end up feeling very loved and attended to and special. That's very appealing.” Trauma Therapy Spending time with dogs can also help those struggling with serious mental health issues such as post-traumatic stress disorder.

    In a study published in March, Florida Atlantic buy prozac fluoxetine online University nursing researcher Cheryl Krause-Parello and her colleagues looked at how walking with shelter dogs impacted veterans suffering from PTSD. Over the course of four weeks, 33 veterans took part in weekly 30-minute dog walks. The scientists measured psychological buy prozac fluoxetine online and physiological stress indicators, like cortisol levels and heart rate variability, among the participants both before and after the strolls. A control group walked with another human instead of a dog.     The study found that walking with dogs tended to decrease signs of PTSD — particularly variability in heart rate — in veterans with severe symptoms more than walking with another human.

    Krause-Parello says that the study is preliminary, but it does suggest animals can help relieve the effects of PTSD. Plus, that animal companionship can have measurable benefits for veterans buy prozac fluoxetine online. She adds that the study was set up so veterans could adopt a shelter job and have their adoption fee covered. Afterwards, several buy prozac fluoxetine online of them choose to do so.            “We had the veterans pick the dog’s names out of the hat,” says Krause-Parello, who also directs Canines Providing Assistance to Wounded Warriors, a research initiative that examines how dogs influence the health and well-being of veterans.

    “We didn’t want anyone to get too attached to one of the animals in case they got adopted. But one of them picked a name out of the hat, walked the dog, and immediately came back and put in an application to adopt that dog. That was really fun.” Pendry notes that it’s important to consider how these interactions impact both the human and the animal. Animal-human interplay can be mutually beneficial, helping improve the health and well-being of the animal while also providing mental health benefits for the human.   “When we’re studying marital functioning, for example, you wouldn’t just ask one spouse, you ideally take both perspectives,” Pendry says.

    “That’s the same with human-animal interactions — we have to consider the well-being and functioning of the animal, because there’s a lot to be gained for them, as well.”       .

    Purchase prozac

    Thin tissue grafts and flexible electronics have a host of purchase prozac applications for wound healing, regenerative medicine and biosensing pop over here. A new device inspired by an octopus's sucker rapidly purchase prozac transfers delicate tissue or electronic sheets to the patient, overcoming a key barrier to clinical application, according to researchers at the University of Illinois at Urbana-Champaign and collaborators."For the last few decades, cell or tissue sheets have been increasingly used to treat injured or diseased tissues. A crucial aspect of tissue transplantation surgery, such as corneal tissue transplantation surgery, is surgical gripping and safe transplantation of soft tissues.

    However, handling these living substances remains a grand challenge because they are fragile and easily crumple when picking them up from the culture media," said study leader Hyunjoon Kong, a professor of chemical and biomolecular engineering at Illinois.Kong's group, along with collaborators at Purdue University, the University of Illinois at Chicago, purchase prozac Chung-Ang University in South Korea, and the Korea Advanced Institute for Science and Technology, published their work in the journal Science Advances.Current methods of transferring the sheets involve growing them on a temperature-sensitive soft polymer that, once transferred, shrinks and releases the thin film. However, this purchase prozac process takes 30-60 minutes to transfer a single sheet, requires skilled technicians and runs the risk of tearing or wrinkling, Kong said."During surgery, surgeons must minimize the risk of damage to soft tissues and transplant quickly, without contamination. Also, transfer of ultrathin materials without wrinkle or damage is another crucial aspect," Kong said.Seeking a way to quickly pick up and release the thin, delicate sheets of cells or electronics without damaging them, the researchers turned to the animal kingdom for inspiration.

    Seeing the way an octopus or squid can pick up both wet and dry objects of all shapes with purchase prozac small pressure changes in their muscle-powered suction cups, rather than a sticky chemical adhesive, gave the researchers an idea.They designed a manipulator made of a temperature-responsive layer of soft hydrogel attached to an electric heater. To pick purchase prozac up a thin sheet, the researchers gently heat the hydrogel to shrink it, then press it to the sheet and turn off the heat. The hydrogel expands slightly, creating suction with the soft tissue or flexible electronic film so it can be lifted and transferred.

    Then they gently place the thin film on the target and turn the heater back on, shrinking the hydrogel and releasing the sheet.The entire process takes about 10 seconds.Next, the researchers hope to integrate sensors into the manipulator, to further take advantage purchase prozac of their soft, bio-inspired design."For example, by integrating pressure sensors with the manipulator, it would be possible to monitor the deformation of target objects during contact and, in turn, adjust the suction force to a level at which materials retain their structural integrity and functionality," Kong said. "By doing so, we can improve purchase prozac the safety and accuracy of handling these materials. In addition, we aim to examine therapeutic efficacy of cells and tissues transferred by the soft manipulator."The National Science Foundation, the National Institutes of Health, the Department of Defense Vision Research Program and the Jump Applied Research in Community Health through Engineering and Simulation endowment supported this work.American and Polish scientists, reporting Oct.

    16 in the journal Science Advances, laid out a novel rationale for COVID-19 drug design -- blocking a molecular "scissor" that the virus uses for virus production and to disable purchase prozac human proteins crucial to the immune response.The researchers are from The University of Texas Health Science Center at San Antonio (UT Health San Antonio) and the Wroclaw University of Science and Technology. Information gleaned by the American team helped Polish chemists to develop two molecules that inhibit the cutter, an enzyme called SARS-CoV-2-PLpro.SARS-CoV-2-PLpro promotes purchase prozac infection by sensing and processing both viral and human proteins, said senior author Shaun K. Olsen, PhD, associate professor of biochemistry and structural biology in the Joe R.

    And Teresa Lozano Long School of Medicine at UT Health San Antonio."This enzyme executes a double-whammy," purchase prozac Dr. Olsen said purchase prozac. "It stimulates the release of proteins that are essential for the virus to replicate, and it also inhibits molecules called cytokines and chemokines that signal the immune system to attack the infection," Dr.

    Olsen said.SARS-CoV-2-PLpro purchase prozac cuts human proteins ubiquitin and ISG15, which help maintain protein integrity. "The enzyme purchase prozac acts like a molecular scissor," Dr. Olsen said.

    "It cleaves ubiquitin purchase prozac and ISG15 away from other proteins, which reverses their normal effects."Dr. Olsen's team, which recently moved to the Long School of Medicine at UT Health San Antonio from the Medical University of South purchase prozac Carolina, solved the three-dimensional structures of SARS-CoV-2-PLpro and the two inhibitor molecules, which are called VIR250 and VIR251. X-ray crystallography was performed at the Argonne National Laboratory near Chicago."Our collaborator, Dr.

    Marcin Drag, and his team developed the inhibitors, which are very efficient at blocking the activity of SARS-CoV-2-PLpro, yet do not recognize other similar enzymes in human cells," purchase prozac Dr. Olsen said purchase prozac. "This is a critical point.

    The inhibitor is specific for this one viral enzyme and doesn't cross-react with human enzymes with a similar function."Specificity will be a key determinant of therapeutic value down the road, he said.The American team purchase prozac also compared SARS-CoV-2-PLpro against similar enzymes from coronaviruses of recent decades, SARS-CoV-1 and MERS. They learned that SARS-CoV-2-PLpro processes ubiquitin and ISG15 much differently than its SARS-1 counterpart."One of the key questions is whether that accounts for some of the purchase prozac differences we see in how those viruses affect humans, if at all," Dr. Olsen said.By understanding similarities and differences of these enzymes in various coronaviruses, it may be possible to develop inhibitors that are effective against multiple viruses, and these inhibitors potentially could be modified when other coronavirus variants emerge in the future, he said.A new study by UBC researchers is set to change international treatment recommendations for people who are newly diagnosed with HIV -- an update that could affect nearly two million people per year worldwide.The study, published today by The Lancet in the journal EClinicalMedicine, was commissioned by the World Health Organization (WHO) as part of a planned update to its guidelines for HIV antiretroviral treatment (ART).

    The study found that dolutegravir is the optimal medication for first-line treatment for people newly diagnosed with HIV, a choice that has not been clear over the past several years."Research supporting the 2016 WHO guidelines suggested that dolutegravir was effective and well tolerated, but its efficacy and safety among key populations, such as pregnant women and people living with both HIV and tuberculosis (TB), remained unclear," said the study's purchase prozac lead author, Dr. Steve Kanters, who completed the purchase prozac research as a PhD candidate in UBC's School of Population and Public Health (SPPH). "In 2018, new research warned of a potentially serious increase in risk of neural tube defects in the children of women who became pregnant while taking this treatment."The risk of adverse reaction meant that, although dolutegravir was found to be favourable compared to other options, it was only recommended as an alternative, with an antiretroviral called efavirenz recommended as the primary treatment.The study team, which included Dr.

    Nick Bansback, purchase prozac associate professor at SPPH, Dr. Aslam Anis, professor at SPPH and director of the Centre for Health purchase prozac Evaluation and Outcome Sciences (CHÉOS), and Dr. Ehsan Karim, assistant professor at SPPH, completed a network meta-analysis of research stemming from 68 available antiretroviral therapy (ART) clinical trials.They found dolutegravir was superior to efavirenz in most outcomes, including viral suppression, tolerability, and safety.

    According to Kanters, the increased odds of purchase prozac viral suppression with dolutegravir could have a significant impact on achieving international goals for HIV treatment. advertisement "We found about a five per cent increase in the probability of viral suppression, which means that more people who start treatment will be able to successfully control their HIV," he said.Another key attribute of dolutegravir is that it is effective in people who are resistant to NNRTI-class antiretrovirals, like efavirenz, a problem that is becoming increasingly common.The analysis also showed that dolutegravir and efavirenz had similar rates of adverse events for pregnant women -- the increased risk of neural tube defects for dolutegravir was estimated to be less than 0.3 per cent."The new evidence on neural purchase prozac tube defects show that the risk with dolutegravir is much more tolerable than previously thought and should quell the initial worry about this drug," said Kanters."Dolutegravir appears to be here to stay as the preferred treatment for people newly diagnosed with HIV," he said. "However, it is important to recognize the good that efavirenz has done over the past two decades, as it helped lead the ART scale-up around the world."Despite the many benefits of dolutegravir, dolutegravir use was associated with increased weight gain, a side effect that could increase the risk of aging-associated comorbidities, like heart attack or stroke."In many places, well-treated HIV has become a chronic condition and we are now seeing people living long lives with HIV," said Kanters.

    "The research community will continue to purchase prozac monitor the effects dolutegravir may have on the healthy aging process."While this study is specifically focused on the optimal treatment for people newly diagnosed with HIV, an upcoming publication will review the evidence in support of switching to dolutegravir for people whose first treatment choice has been unsuccessful in controlling their infection. This recommendation could mean improved treatment for the many people living with HIV around the world who are unable to achieve viral suppression purchase prozac despite being on treatment.People with multiple sclerosis (MS) gradually develop increasing functional impairment. Researchers at Karolinska Institutet have now found a possible explanation for the progressive course of the disease in mice and how it can be reversed.

    The study, which is published in Science Immunology, can prove valuable to future treatments.MS is a chronic inflammatory disease of the central nervous system (CNS) and one of the main purchase prozac causes of neurological functional impairment.The disease is generally diagnosed between 20 and 30 years of age. It can purchase prozac cause severe neurological symptoms, such as loss of sensation and trembling, difficulties walking and maintaining balance, memory failure and visual impairment.MS is a life-long disease with symptoms that most often gradually worsen over time.In the majority of cases the disease comes in bouts with a certain amount of subsequent recovery. A gradual loss of function with time is, however, inevitable.

    Research has made great progress in treatments that reduce the frequency and damaging effects of these bouts."Despite these important breakthroughs, the disease generally worsens when the patient has had it for 10 to 20 years," says Maja purchase prozac Jagodic, docent of experimental medicine at the Department of Clinical Neuroscience and the Centre for Molecular Medicine, Karolinska Institutet. "There is currently only one, recently approved, treatment purchase prozac for what is called the secondary progressive phase. The mechanisms behind this progressive phase require more research."Researchers at Karolinska Institutet have now shown that recovery from MS-like symptoms in mice depends on the ability of the CNS's own immune cells -- microglia -- to break down the remains of damaged cells, such as myelin.The processes was interrupted when the researchers removed a so-called autophagy gene, Atg7.

    Autophagy is a process where cells normally break down and recycle their own proteins and other structural components.Without Atg7 the ability of the microglia to clean away purchase prozac tissue residues created by the inflammation was reduced. These residues accumulated over time, which is a possible purchase prozac explanation for the progressiveness of the disease.The study also shows how microglia from aged mice resemble the cells from young mice that lacked Atg7 in terms of deficiencies in this process, which had a negative effect on the course of the disease.This is a significant result since increasing age is an important risk factor in the progressive phase of MS. The researchers also show how this process can be reversed."The plant and fungi-derived sugar Trehalose restores the functional breakdown of myelin residues, stops the progression and leads to recovery from MS-like disease." says doctoral student Rasmus Berglund.

    "By enhancing this process we hope one day to be able to treat purchase prozac and prevent age-related aspects of neuroinflammatory conditions." Story Source. Materials provided purchase prozac by Karolinska Institutet. Note.

    Content may be edited for style and length.Droplets of fat inside our cells are helping the body's own defence system fight back against infection, University of Queensland researchers have discovered.The international collaboration between UQ Institute for Molecular Bioscience researchers Professor Robert Parton and Professor Matt Sweet, and the University of Barcelona's Professor Albert Pol found that these fat droplets are both a food source and weapon against bacterial invaders."It was previously thought that bacteria were merely using the lipid droplets to feed on, but we have discovered these fatty droplets purchase prozac are involved in the battle between the pathogens and our cells," Professor Parton said."Fat is part of the cell's arsenal -- cells manufacture toxic proteins, package them into the lipid droplets, then fire them at the intruders."This is a new way that cells are protecting themselves, using fats as a covert weapon, and giving us new insights into ways of fighting infection."With antibiotic-resistant superbugs on the rise, researchers are determined to find alternative ways to fight infection. advertisement One possibility is ramping up the body's natural defences."We showed that upon infection of white blood cells called macrophages, lipid droplets move to the part of the macrophage where the bacteria are present," Professor Sweet said.The bacterial infection also changed the way that white blood cells used energy."Lipid droplets can be used as a fuel source for mitochondria when there aren't enough other nutrients," Professor Sweet said."During an infection, lipid droplets move away from the mitochondria and attack the bacteria instead, altering metabolism of the cell."Cell purchase prozac biologist Professor Parton was inspired to continue this research after the phenomenon was seen in fruit flies. advertisement "Most people thought the lipid droplets were 'blobs of fat', only useful for energy storage but now we are seeing that they act as metabolic switches in the cell, defend against infection and much more -- there are now entire scientific conferences of researchers working on them," he said."Our next step is to find out how the lipid droplets target the bacteria."By understanding the body's natural defences, we can develop new therapies that don't rely on antibiotics to fight drug-resistant infections."VIDEO -- https://youtu.be/WTJc7oQFezU Story Source.

    Materials provided by University of Queensland purchase prozac. Note. Content may be edited for style and length..

    Thin tissue grafts buy prozac fluoxetine online and flexible electronics have a host of applications for wound healing, regenerative medicine and biosensing. A new device inspired by an octopus's sucker rapidly buy prozac fluoxetine online transfers delicate tissue or electronic sheets to the patient, overcoming a key barrier to clinical application, according to researchers at the University of Illinois at Urbana-Champaign and collaborators."For the last few decades, cell or tissue sheets have been increasingly used to treat injured or diseased tissues. A crucial aspect of tissue transplantation surgery, such as corneal tissue transplantation surgery, is surgical gripping and safe transplantation of soft tissues. However, handling these living substances remains a grand challenge because they are fragile and easily crumple when picking them up from the culture media," said study leader Hyunjoon Kong, a professor of chemical and biomolecular engineering at Illinois.Kong's group, along with collaborators at Purdue University, the University of Illinois at Chicago, Chung-Ang University in South Korea, and the Korea Advanced Institute for Science and Technology, published their work in the journal Science Advances.Current methods of transferring the sheets involve growing them on a temperature-sensitive soft polymer that, once transferred, shrinks and releases the thin film buy prozac fluoxetine online. However, this process takes 30-60 minutes to transfer a single sheet, requires skilled technicians and runs the risk of tearing or wrinkling, Kong said."During surgery, surgeons must minimize the risk of damage buy prozac fluoxetine online to soft tissues and transplant quickly, without contamination.

    Also, transfer of ultrathin materials without wrinkle or damage is another crucial aspect," Kong said.Seeking a way to quickly pick up and release the thin, delicate sheets of cells or electronics without damaging them, the researchers turned to the animal kingdom for inspiration. Seeing the way an octopus or squid can pick up both wet buy prozac fluoxetine online and dry objects of all shapes with small pressure changes in their muscle-powered suction cups, rather than a sticky chemical adhesive, gave the researchers an idea.They designed a manipulator made of a temperature-responsive layer of soft hydrogel attached to an electric heater. To pick up a thin sheet, the researchers gently heat buy prozac fluoxetine online the hydrogel to shrink it, then press it to the sheet and turn off the heat. The hydrogel expands slightly, creating suction with the soft tissue or flexible electronic film so it can be lifted and transferred. Then they gently place the thin film on the target and turn the heater back on, shrinking the hydrogel and releasing the sheet.The entire process takes about 10 seconds.Next, the researchers hope to integrate sensors into the manipulator, to further take advantage of their soft, bio-inspired design."For example, by integrating pressure sensors with the manipulator, it would be possible to monitor buy prozac fluoxetine online the deformation of target objects during contact and, in turn, adjust the suction force to a level at which materials retain their structural integrity and functionality," Kong said.

    "By doing so, we can improve the safety and buy prozac fluoxetine online accuracy of handling these materials. In addition, we aim to examine therapeutic efficacy of cells and tissues transferred by the soft manipulator."The National Science Foundation, the National Institutes of Health, the Department of Defense Vision Research Program and the Jump Applied Research in Community Health through Engineering and Simulation endowment supported this work.American and Polish scientists, reporting Oct. 16 in the journal Science Advances, laid out a novel rationale for COVID-19 drug design -- blocking a molecular "scissor" that the virus uses for virus production and to disable human proteins crucial to the immune response.The researchers are from The University of buy prozac fluoxetine online Texas Health Science Center at San Antonio (UT Health San Antonio) and the Wroclaw University of Science and Technology. Information gleaned by the American team helped Polish chemists to develop two molecules that inhibit the cutter, an enzyme called SARS-CoV-2-PLpro.SARS-CoV-2-PLpro promotes buy prozac fluoxetine online infection by sensing and processing both viral and human proteins, said senior author Shaun K. Olsen, PhD, associate professor of biochemistry and structural biology in the Joe R.

    And Teresa Lozano buy prozac fluoxetine online Long School of Medicine at UT Health San Antonio."This enzyme executes a double-whammy," Dr. Olsen said buy prozac fluoxetine online. "It stimulates the release of proteins that are essential for the virus to replicate, and it also inhibits molecules called cytokines and chemokines that signal the immune system to attack the infection," Dr. Olsen said.SARS-CoV-2-PLpro cuts human proteins ubiquitin and ISG15, which help buy prozac fluoxetine online maintain protein integrity. "The enzyme acts like a molecular scissor," buy prozac fluoxetine online Dr.

    Olsen said. "It cleaves ubiquitin and ISG15 away from other proteins, which reverses their buy prozac fluoxetine online normal effects."Dr. Olsen's team, which recently moved buy prozac fluoxetine online to the Long School of Medicine at UT Health San Antonio from the Medical University of South Carolina, solved the three-dimensional structures of SARS-CoV-2-PLpro and the two inhibitor molecules, which are called VIR250 and VIR251. X-ray crystallography was performed at the Argonne National Laboratory near Chicago."Our collaborator, Dr. Marcin Drag, and his team developed the inhibitors, which buy prozac fluoxetine online are very efficient at blocking the activity of SARS-CoV-2-PLpro, yet do not recognize other similar enzymes in human cells," Dr.

    Olsen said buy prozac fluoxetine online. "This is a critical point. The inhibitor is specific for this one buy prozac fluoxetine online viral enzyme and doesn't cross-react with human enzymes with a similar function."Specificity will be a key determinant of therapeutic value down the road, he said.The American team also compared SARS-CoV-2-PLpro against similar enzymes from coronaviruses of recent decades, SARS-CoV-1 and MERS. They learned that SARS-CoV-2-PLpro processes ubiquitin and ISG15 much differently than its SARS-1 counterpart."One buy prozac fluoxetine online of the key questions is whether that accounts for some of the differences we see in how those viruses affect humans, if at all," Dr. Olsen said.By understanding similarities and differences of these enzymes in various coronaviruses, it may be possible to develop inhibitors that are effective against multiple viruses, and these inhibitors potentially could be modified when other coronavirus variants emerge in the future, he said.A new study by UBC researchers is set to change international treatment recommendations for people who are newly diagnosed with HIV -- an update that could affect nearly two million people per year worldwide.The study, published today by The Lancet in the journal EClinicalMedicine, was commissioned by the World Health Organization (WHO) as part of a planned update to its guidelines for HIV antiretroviral treatment (ART).

    The study found that dolutegravir is the optimal medication for first-line treatment for people newly diagnosed with HIV, a choice that has not been clear over the past several years."Research supporting the 2016 WHO guidelines suggested that dolutegravir was effective and well tolerated, but its efficacy and safety among key populations, such as pregnant women and people living with both HIV and buy prozac fluoxetine online tuberculosis (TB), remained unclear," said the study's lead author, Dr. Steve Kanters, who completed the research as a PhD candidate in UBC's School of Population and buy prozac fluoxetine online Public Health (SPPH). "In 2018, new research warned of a potentially serious increase in risk of neural tube defects in the children of women who became pregnant while taking this treatment."The risk of adverse reaction meant that, although dolutegravir was found to be favourable compared to other options, it was only recommended as an alternative, with an antiretroviral called efavirenz recommended as the primary treatment.The study team, which included Dr. Nick Bansback, associate professor at SPPH, Dr buy prozac fluoxetine online. Aslam Anis, professor at SPPH and director of the Centre for Health Evaluation buy prozac fluoxetine online and Outcome Sciences (CHÉOS), and Dr.

    Ehsan Karim, assistant professor at SPPH, completed a network meta-analysis of research stemming from 68 available antiretroviral therapy (ART) clinical trials.They found dolutegravir was superior to efavirenz in most outcomes, including viral suppression, tolerability, and safety. According to Kanters, the increased odds of viral suppression with dolutegravir could have a significant buy prozac fluoxetine online impact on achieving international goals for HIV treatment. advertisement "We found about a five per cent increase in the probability of viral suppression, which means that more people who start treatment will be able to successfully control their HIV," he said.Another key attribute of dolutegravir is that it is effective in people who are resistant to NNRTI-class antiretrovirals, like efavirenz, a problem that is becoming increasingly common.The analysis also showed that dolutegravir and efavirenz had similar rates of adverse events for pregnant women -- the increased risk of neural tube defects for dolutegravir was estimated to be less than 0.3 per cent."The new evidence on neural tube defects show that the risk with dolutegravir is much more tolerable than previously buy prozac fluoxetine online thought and should quell the initial worry about this drug," said Kanters."Dolutegravir appears to be here to stay as the preferred treatment for people newly diagnosed with HIV," he said. "However, it is important to recognize the good that efavirenz has done over the past two decades, as it helped lead the ART scale-up around the world."Despite the many benefits of dolutegravir, dolutegravir use was associated with increased weight gain, a side effect that could increase the risk of aging-associated comorbidities, like heart attack or stroke."In many places, well-treated HIV has become a chronic condition and we are now seeing people living long lives with HIV," said Kanters. "The research community will continue to monitor the effects dolutegravir may have on the healthy aging process."While this study is specifically focused on the optimal treatment for people newly diagnosed with HIV, an upcoming publication will review the evidence in support of switching to dolutegravir for people whose first treatment choice has been unsuccessful in controlling buy prozac fluoxetine online their infection.

    This recommendation could mean improved treatment for buy prozac fluoxetine online the many people living with HIV around the world who are unable to achieve viral suppression despite being on treatment.People with multiple sclerosis (MS) gradually develop increasing functional impairment. Researchers at Karolinska Institutet have now found a possible explanation for the progressive course of the disease in mice and how it can be reversed. The study, which is published in Science Immunology, can prove valuable to future treatments.MS is a chronic inflammatory disease of the central nervous system (CNS) and one of the main causes of neurological functional impairment.The disease is buy prozac fluoxetine online generally diagnosed between 20 and 30 years of age. It can cause severe neurological symptoms, such as loss of sensation and buy prozac fluoxetine online trembling, difficulties walking and maintaining balance, memory failure and visual impairment.MS is a life-long disease with symptoms that most often gradually worsen over time.In the majority of cases the disease comes in bouts with a certain amount of subsequent recovery. A gradual loss of function with time is, however, inevitable.

    Research has made great progress in treatments that reduce the frequency and damaging effects of these bouts."Despite these important breakthroughs, the disease generally worsens when the patient has had it for 10 to 20 years," says Maja Jagodic, docent of experimental medicine at the Department of Clinical Neuroscience and the Centre for Molecular Medicine, buy prozac fluoxetine online Karolinska Institutet. "There is currently only one, recently approved, treatment for what buy prozac fluoxetine online is called the secondary progressive phase. The mechanisms behind this progressive phase require more research."Researchers at Karolinska Institutet have now shown that recovery from MS-like symptoms in mice depends on the ability of the CNS's own immune cells -- microglia -- to break down the remains of damaged cells, such as myelin.The processes was interrupted when the researchers removed a so-called autophagy gene, Atg7. Autophagy is a process where cells normally break down and recycle their own proteins and other buy prozac fluoxetine online structural components.Without Atg7 the ability of the microglia to clean away tissue residues created by the inflammation was reduced. These residues accumulated over time, which is a possible explanation for the progressiveness of the disease.The study also shows how microglia from aged mice resemble the cells from young mice buy prozac fluoxetine online that lacked Atg7 in terms of deficiencies in this process, which had a negative effect on the course of the disease.This is a significant result since increasing age is an important risk factor in the progressive phase of MS.

    The researchers also show how this process can be reversed."The plant and fungi-derived sugar Trehalose restores the functional breakdown of myelin residues, stops the progression and leads to recovery from MS-like disease." says doctoral student Rasmus Berglund. "By enhancing this process we hope one buy prozac fluoxetine online day to be able to treat and prevent age-related aspects of neuroinflammatory conditions." Story Source. Materials provided by Karolinska buy prozac fluoxetine online Institutet. Note. Content may be edited for style and length.Droplets of fat inside our cells are helping the body's own defence buy prozac fluoxetine online system fight back against infection, University of Queensland researchers have discovered.The international collaboration between UQ Institute for Molecular Bioscience researchers Professor Robert Parton and Professor Matt Sweet, and the University of Barcelona's Professor Albert Pol found that these fat droplets are both a food source and weapon against bacterial invaders."It was previously thought that bacteria were merely using the lipid droplets to feed on, but we have discovered these fatty droplets are involved in the battle between the pathogens and our cells," Professor Parton said."Fat is part of the cell's arsenal -- cells manufacture toxic proteins, package them into the lipid droplets, then fire them at the intruders."This is a new way that cells are protecting themselves, using fats as a covert weapon, and giving us new insights into ways of fighting infection."With antibiotic-resistant superbugs on the rise, researchers are determined to find alternative ways to fight infection.

    advertisement One possibility is ramping up the body's natural defences."We showed that upon infection of white blood cells called macrophages, lipid droplets move to the part of the macrophage where the bacteria are present," Professor Sweet said.The bacterial infection also changed the way that white blood cells used energy."Lipid droplets can be used as a fuel source for mitochondria when there aren't enough other nutrients," Professor Sweet said."During an infection, lipid droplets move away from the mitochondria and attack the bacteria instead, altering metabolism of the cell."Cell biologist Professor Parton buy prozac fluoxetine online was inspired to continue this research after the phenomenon was seen in fruit flies. advertisement "Most people thought the lipid droplets were 'blobs of fat', only useful for energy storage but now we are seeing that they act as metabolic switches in the cell, defend against infection and much more -- there are now entire scientific conferences of researchers working on them," he said."Our next step is to find out how the lipid droplets target the bacteria."By understanding the body's natural defences, we can develop new therapies that don't rely on antibiotics to fight drug-resistant infections."VIDEO -- https://youtu.be/WTJc7oQFezU Story Source. Materials provided by buy prozac fluoxetine online University of Queensland. Note. Content may be edited for style and length..

    Will prozac help me lose weight

    Specificity of SARS-CoV-2 Antibody Assays Both assays measuring pan-Ig will prozac help me lose weight navigate here antibodies had low numbers of false positives among samples collected in 2017. There were 0 and 1 false positives for the two assays among 472 samples, results that compared favorably will prozac help me lose weight with those obtained with the single IgM anti-N and IgG anti-N assays (Table S3). Because of the low prevalence of SARS-CoV-2 infection in Iceland, we required positive results from both pan-Ig antibody assays for a sample to be considered seropositive (see Supplementary Methods in Supplementary Appendix 1). None of the samples collected in early 2020 group were seropositive, which indicates that the virus had will prozac help me lose weight not spread widely in Iceland before February 2020.

    SARS-CoV-2 Antibodies among qPCR-Positive Persons Figure 2. Figure 2 will prozac help me lose weight. Antibody Prevalence and Titers among qPCR-Positive Cases as a Function of Time since Diagnosis will prozac help me lose weight by qPCR. Shown are the percentages of samples positive for both pan-Ig antibody assays and the antibody titers.

    Red denotes the count or percentage of samples among persons during their hospitalization (249 samples from 48 persons), and blue denotes the count will prozac help me lose weight or percentage of samples among persons after they were declared recovered (1853 samples from 1215 persons). Vertical bars denote 95% confidence intervals. The dashed lines indicated the thresholds for a test to be will prozac help me lose weight declared positive. OD denotes optical density, and RBD receptor will prozac help me lose weight binding domain.Table 1.

    Table 1. Prevalence of SARS-CoV-2 Antibodies will prozac help me lose weight by Sample Collection as Measured by Two Pan-Ig Antibody Assays. Twenty-five days after diagnosis by qPCR, more than 90% of samples from recovered persons tested positive with both pan-Ig antibody assays, and the percentage of persons testing positive remained stable thereafter (Figure 2 and Fig. S2).

    Hospitalized persons seroconverted more frequently and quickly after qPCR diagnosis than did nonhospitalized persons (Figure 2 and Fig. S3). Of 1215 persons who had recovered (on the basis of results for the most recently obtained sample from persons for whom we had multiple samples), 1107 were seropositive (91.1%. 95% confidence interval [CI], 89.4 to 92.6) (Table 1 and Table S4).

    Since some diagnoses may have been made on the basis of false positive qPCR results, we determined that 91.1% represents the lower bound of sensitivity of the combined pan-Ig tests for the detection of SARS-CoV-2 antibodies among recovered persons. Table 2. Table 2. Results of Repeated Pan-Ig Antibody Tests among Recovered qPCR-Diagnosed Persons.

    Among the 487 recovered persons with two or more samples, 19 (4%) had different pan-Ig antibody test results at different time points (Table 2 and Fig. S4). It is notable that of the 22 persons with an early sample that tested negative for both pan-Ig antibodies, 19 remained negative at the most recent test date (again, for both antibodies). One person tested positive for both pan-Ig antibodies in the first test and negative for both in the most recent test.

    The longitudinal changes in antibody levels among recovered persons were consistent with the cross-sectional results (Fig. S5). Antibody levels were higher in the last sample than in the first sample when the antibodies were measured with the two pan-Ig assays, slightly lower than in the first sample when measured with IgG anti-N and IgG anti-S1 assays, and substantially lower than in the first sample when measured with IgM anti-N and IgA anti-S1 assays. IgG anti-N, IgM anti-N, IgG anti-S1, and IgA anti-S1 antibody levels were correlated among the qPCR-positive persons (Figs.

    S5 and S6 and Table S5). Antibody levels measured with both pan-Ig antibody assays increased over the first 2 months after qPCR diagnosis and remained at a plateau over the next 2 months of the study. IgM anti-N antibody levels increased rapidly soon after diagnosis and then fell rapidly and were generally not detected after 2 months. IgA anti-S1 antibodies decreased 1 month after diagnosis and remained detectable thereafter.

    IgG anti-N and anti-S1 antibody levels increased during the first 6 weeks after diagnosis and then decreased slightly. SARS-CoV-2 Infection in Quarantine Table 3. Table 3. SARS-CoV-2 Infection among Quarantined Persons According to Exposure Type and Presence of Symptoms.

    Of the 1797 qPCR-positive Icelanders, 1088 (61%) were in quarantine when SARS-CoV-2 infection was diagnosed by qPCR. We tested for antibodies among 4222 quarantined persons who had not tested qPCR-positive (they had received a negative result by qPCR or had simply not been tested). Of those 4222 quarantined persons, 97 (2.3%. 95% CI, 1.9 to 2.8) were seropositive (Table 1).

    Those with household exposure were 5.2 (95% CI, 3.3 to 8.0) times more likely to be seropositive than those with other types of exposure (Table 3). Similarly, a positive result by qPCR for those with household exposure was 5.2 (95% CI, 4.5 to 6.1) times more likely than for those with other types of exposure. When these two sets of results (qPCR-positive and seropositive) were combined, we calculated that 26.6% of quarantined persons with household exposure and 5.0% of quarantined persons without household exposure were infected. Those who had symptoms during quarantine were 3.2 (95% CI, 1.7 to 6.2) times more likely to be seropositive and 18.2 times (95% CI, 14.8 to 22.4) more likely to test positive with qPCR than those without symptoms.

    We also tested persons in two regions of Iceland affected by cluster outbreaks. In a SARS-CoV-2 cluster in Vestfirdir, 1.4% of residents were qPCR-positive and 10% of residents were quarantined. We found that none of the 326 persons outside quarantine who had not been tested by qPCR (or who tested negative) were seropositive. In a cluster in Vestmannaeyjar, 2.3% of residents were qPCR-positive and 13% of residents were quarantined.

    Of the 447 quarantined persons who had not received a qPCR-positive result, 4 were seropositive (0.9%. 95% CI, 0.3 to 2.1). Of the 663 outside quarantine in Vestmannaeyjar, 3 were seropositive (0.5%. 95% CI, 0.1 to 0.2%).

    SARS-CoV-2 Seroprevalence in Iceland None of the serum samples collected from 470 healthy Icelanders between February 18 and March 9, 2020, tested positive for both pan-Ig antibodies, although four were positive for the pan-Ig anti-N assay (0.9%), a finding that suggests that the virus had not spread widely in Iceland before March 9. Of the 18,609 persons tested for SARS-CoV-2 antibodies through contact with the Icelandic health care system for reasons other than Covid-19, 39 were positive for both pan-Ig antibody assays (estimated seroprevalence by weighting the sample on the basis of residence, sex, and 10-year age category, 0.3%. 95% CI, 0.2 to 0.4). There were regional differences in the percentages of qPCR-positive persons across Iceland that were roughly proportional to the percentage of people quarantined (Table S6).

    However, after exclusion of the qPCR-positive and quarantined persons, the percentage of persons who tested positive for SARS-CoV-2 antibodies did not correlate with the percentage of those who tested positive by qPCR. The estimated seroprevalence in the random sample collection from Reykjavik (0.4%. 95% CI, 0.3 to 0.6) was similar to that in the Health Care group (0.3%. 95% CI, 0.2 to 0.4) (Table S6).

    We calculate that 0.5% of the residents of Iceland have tested positive with qPCR. The 2.3% with SARS-CoV-2 seroconversion among persons in quarantine extrapolates to 0.1% of Icelandic residents. On the basis of this finding and the seroprevalence from the Health Care group, we estimate that 0.9% (95% CI, 0.8 to 0.9) of the population of Iceland has been infected by SARS-CoV-2. Approximately 56% of all SARS-CoV-2 infections were therefore diagnosed by qPCR, 14% occurred in quarantine without having been diagnosed with qPCR, and the remaining 30% of infections occurred outside quarantine and were not detected by qPCR.

    Deaths from Covid-19 in Iceland In Iceland, 10 deaths have been attributed to Covid-19, which corresponds to 3 deaths per 100,000 nationwide. Among the qPCR-positive cases, 0.6% (95% CI, 0.3 to 1.0) were fatal. Using the 0.9% prevalence of SARS-CoV-2 infection in Iceland as the denominator, however, we calculate an infection fatality risk of 0.3% (95% CI, 0.2 to 0.6). Stratified by age, the infection fatality risk was substantially lower in those 70 years old or younger (0.1%.

    95% CI, 0.0 to 0.3) than in those over 70 years of age (4.4%. 95% CI, 1.9 to 8.4) (Table S7). Age, Sex, Clinical Characteristics, and Antibody Levels Table 4. Table 4.

    Association of Existing Conditions and Covid-19 Severity with SARS-CoV-2 Antibody Levels among Recovered Persons. SARS-CoV-2 antibody levels were higher in older people and in those who were hospitalized (Table 4, and Table S8 [described in Supplementary Appendix 1 and available in Supplementary Appendix 2]). Pan-Ig anti–S1-RBD and IgA anti-S1 levels were lower in female persons. Of the preexisting conditions, and after adjustment for multiple testing, we found that body-mass index, smoking status, and use of antiinflammatory medication were associated with SARS-CoV-2 antibody levels.

    Body-mass index correlated positively with antibody levels. Smokers and users of antiinflammatory medication had lower antibody levels. With respect to clinical characteristics, antibody levels were most strongly associated with hospitalization and clinical severity, followed by clinical symptoms such as fever, maximum temperature reading, cough, and loss of appetite. Severity of these individual symptoms, with the exception of loss of energy, was associated with higher antibody levels.Trial Population Table 1.

    Table 1. Demographic Characteristics of the Participants in the NVX-CoV2373 Trial at Enrollment. The trial was initiated on May 26, 2020. 134 participants underwent randomization between May 27 and June 6, 2020, including 3 participants who were to serve as backups for sentinel dosing and who immediately withdrew from the trial without being vaccinated (Fig.

    S1). Of the 131 participants who received injections, 23 received placebo (group A), 25 received 25-μg doses of rSARS-CoV-2 (group B), 29 received 5-μg doses of rSARS-CoV-2 plus Matrix-M1, including three sentinels (group C), 28 received 25-μg doses of rSARS-CoV-2 plus Matrix-M1, including three sentinels (group D), and 26 received a single 25-μg dose of rSARS-CoV-2 plus Matrix-M1 followed by a single dose of placebo (group E). All 131 participants received their first vaccination on day 0, and all but 3 received their second vaccination at least 21 days later. Exceptions include 2 in the placebo group (group A) who withdrew consent (unrelated to any adverse event) and 1 in the 25-μg rSARS-CoV-2 + Matrix-M1 group (group D) who had an unsolicited adverse event (mild cellulitis.

    See below). Demographic characteristics of the participants are presented in Table 1. Of note, missing data were infrequent. Safety Outcomes No serious adverse events or adverse events of special interest were reported, and vaccination pause rules were not implemented.

    As noted above, one participant did not receive a second vaccination owing to an unsolicited adverse event, mild cellulitis, that was associated with infection after an intravenous cannula placement to address an unrelated mild adverse event that occurred during the second week of follow-up. Second vaccination was withheld because the participant was still recovering and receiving antibiotics. This participant remains in the trial. Figure 2.

    Figure 2. Solicited Local and Systemic Adverse Events. The percentage of participants in each vaccine group (groups A, B, C, D, and E) with adverse events according to the maximum FDA toxicity grade (mild, moderate, or severe) during the 7 days after each vaccination is plotted for solicited local (Panel A) and systemic (Panel B) adverse events. There were no grade 4 (life-threatening) events.

    Participants who reported 0 events make up the remainder of the 100% calculation (not displayed). Excluded were the three sentinel participants in groups C (5 μg + Matrix-M1, 5 μg + Matrix-M1) and D (25 μg + Matrix-M1, 25 μg + Matrix-M1), who received the trial vaccine in an open-label manner (see Table S7 for complete safety data on all participants).Overall reactogenicity was largely absent or mild, and second vaccinations were neither withheld nor delayed due to reactogenicity. After the first vaccination, local and systemic reactogenicity was absent or mild in the majority of participants (local. 100%, 96%, 89%, 84%, and 88% of participants in groups A, B, C, D, and E, respectively.

    Systemic. 91%, 92%, 96%, 68%, and 89%) who were unaware of treatment assignment (Figure 2 and Table S7). Two participants (2%), one each in groups D and E, had severe adverse events (headache, fatigue, and malaise). Two participants, one each in groups A and E, had reactogenicity events (fatigue, malaise, and tenderness) that extended 2 days after day 7.

    After the second vaccination, local and systemic reactogenicity were absent or mild in the majority of participants in the five groups (local. 100%, 100%, 65%, 67%, and 100% of participants, respectively. Systemic. 86%, 84%, 73%, 58%, and 96%) who were unaware of treatment assignment.

    One participant, in group D, had a severe local event (tenderness), and eight participants, one or two participants in each group, had severe systemic events. The most common severe systemic events were joint pain and fatigue. Only one participant, in group D, had fever (temperature, 38.1°C) after the second vaccination, on day 1 only. No adverse event extended beyond 7 days after the second vaccination.

    Of note, the mean duration of reactogenicity events was 2 days or less for both the first vaccination and second vaccination periods. Laboratory abnormalities of grade 2 or higher occurred in 13 participants (10%). 9 after the first vaccination and 4 after the second vaccination (Table S8). Abnormal laboratory values were not associated with any clinical manifestations and showed no worsening with repeat vaccination.

    Six participants (5%. Five women and one man) had grade 2 or higher transient reductions in hemoglobin from baseline, with no evidence of hemolysis or microcytic anemia and with resolution within 7 to 21 days. Of the six, two had an absolute hemoglobin value (grade 2) that resolved or stabilized during the testing period. Four participants (3%), including one who had received placebo, had elevated liver enzymes that were noted after the first vaccination and resolved within 7 to 14 days (i.e., before the second vaccination).

    Vital signs remained stable immediately after vaccination and at all visits. Unsolicited adverse events (Table S9) were predominantly mild in severity (in 71%, 91%, 83%, 90%, and 82% of participants in groups A, B, C, D, and E, respectively) and were similarly distributed across the groups receiving adjuvanted and unadjuvanted vaccine. There were no reports of severe adverse events. Immunogenicity Outcomes Figure 3.

    Figure 3. SARS-CoV-2 Anti-Spike IgG and Neutralizing Antibody Responses. Shown are geometric mean anti-spike IgG enzyme-linked immunosorbent assay (ELISA) unit responses to recombinant severe acute respiratory syndrome coronavirus 2 (rSARS-CoV-2) protein antigens (Panel A) and wild-type SARS-CoV-2 microneutralization assay at an inhibitory concentration greater than 99% (MN IC>99%) titer responses (Panel B) at baseline (day 0), 3 weeks after the first vaccination (day 21), and 2 weeks after the second vaccination (day 35) for the placebo group (group A), the 25-μg unadjuvanted group (group B), the 5-μg and 25-μg adjuvanted groups (groups C and D, respectively), and the 25-μg adjuvanted and placebo group (group E). Diamonds and whisker endpoints represent geometric mean titer values and 95% confidence intervals, respectively.

    The Covid-19 human convalescent serum panel includes specimens from PCR-confirmed Covid-19 participants, obtained from Baylor College of Medicine (29 specimens for ELISA and 32 specimens for MN IC>99%), with geometric mean titer values according to Covid-19 severity. The severity of Covid-19 is indicated by the colors of the dots for hospitalized patients (including those in intensive care), symptomatic outpatients (with samples collected in the emergency department), and asymptomatic patients who had been exposed to Covid-19 (with samples collected during contact and exposure assessment). Mean values (in black) for human convalescent serum are depicted next to (and of same color as) the category of Covid-19 patients, with the overall mean shown above the scatter plot (in black). For each trial vaccine group, the mean at day 35 is depicted above the scatterplot.ELISA anti-spike IgG geometric mean ELISA units (GMEUs) ranged from 105 to 116 at day 0.

    By day 21, responses had occurred for all adjuvanted regimens (1984, 2626, and 3317 GMEUs for groups C, D, and E, respectively), and geometric mean fold rises (GMFRs) exceeded those induced without adjuvant by a factor of at least 10 (Figure 3 and Table S10). Within 7 days after the second vaccination with adjuvant (day 28. Groups C and D), GMEUs had further increased by a factor of 8 (to 15,319 and 20,429, respectively) over responses seen with the first vaccination, and within 14 days (day 35), responses had more than doubled yet again (to 63,160 and 47,521, respectively), achieving GMFRs that were approximately 100 times greater than those observed with rSARS-CoV-2 alone. A single vaccination with adjuvant achieved GMEU levels similar to those in asymptomatic (exposed) patients with Covid-19 (1661), and a second vaccination with adjuvant achieved GMEU levels that exceeded those in convalescent serum from symptomatic outpatients with Covid-19 (7420) by a factor of at least 6 and rose to levels similar to those in convalescent serum from patients hospitalized with Covid-19 (53,391).

    The responses in the two-dose 5-μg and 25-μg adjuvanted vaccine regimens were similar, a finding that highlights the role of adjuvant dose sparing. Neutralizing antibodies were undetectable before vaccination and had patterns of response similar to those of anti-spike antibodies after vaccination with adjuvant (Figure 3 and Table S11). After the first vaccination (day 21), GMFRs were approximately 5 times greater with adjuvant (5.2, 6.3, and 5.9 for groups C, D, and E, respectively) than without adjuvant (1.1). By day 35, second vaccinations with adjuvant induced an increase more than 100 times greater (195 and 165 for groups C and D, respectively) than single vaccinations without adjuvant.

    When compared with convalescent serum, second vaccinations with adjuvant resulted in GMT levels approximately 4 times greater (3906 and 3305 for groups C and D, respectively) than those in symptomatic outpatients with Covid-19 (837) and approached the magnitude of levels observed in hospitalized patients with COVID-19 (7457). At day 35, ELISA anti-spike IgG GMEUs and neutralizing antibodies induced by the two-dose 5-μg and 25-μg adjuvanted vaccine regimens were 4 to 6 times greater than the geometric mean convalescent serum measures (8344 and 983, respectively). Figure 4 effects of prozac during pregnancy. Figure 4.

    Correlation of Anti-Spike IgG and Neutralizing Antibody Responses. Shown are scatter plots of 100% wild-type neutralizing antibody responses and anti-spike IgG ELISA unit responses at 3 weeks after the first vaccination (day 21) and 2 weeks after the second vaccination (day 35) for the two-dose 25-μg unadjuvanted vaccine (group B. Panel A), the combined two-dose 5-μg and 25-μg adjuvanted vaccine (groups C and D, respectively. Panel B), and convalescent serum from patients with Covid-19 (Panel C).

    In Panel C, the severity of Covid-19 is indicated by the colors of the dots for hospitalized patients (including those in intensive care), symptomatic outpatients (with samples collected in the emergency department), and asymptomatic patients who had been exposed to Covid-19 (with samples collected during contact and exposure assessment).A strong correlation was observed between neutralizing antibody titers and anti-spike IgG GMEUs with adjuvanted vaccine at day 35 (correlation, 0.95) (Figure 4), a finding that was not observed with unadjuvanted vaccine (correlation, 0.76) but was similar to that of convalescent serum (correlation, 0.96). Two-dose regimens of 5-μg and 25-μg rSARS-CoV-2 plus Matrix-M1 produced similar magnitudes of response, and every participant had seroconversion according to either assay measurement. Reverse cumulative-distribution curves for day 35 are presented in Figure S2. Figure 5.

    Figure 5. RSARS-CoV-2 CD4+ T-cell Responses with or without Matrix-M1 Adjuvant. Frequencies of antigen-specific CD4+ T cells producing T helper 1 (Th1) cytokines interferon-gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α), and interleukin-2 and for T helper 2 (Th2) cytokines interleukin-5 and interleukin-13 indicated cytokines from four participants each in the placebo (group A), 25-μg unadjuvanted (group B), 5-μg adjuvanted (group C), and 25-μg adjuvanted (group D) groups at baseline (day 0) and 1 week after the second vaccination (day 28) after stimulation with the recombinant spike protein. €œAny 2Th1” indicates CD4+ T cells that can produce two types of Th1 cytokines at the same time.

    €œAll 3 Th1” indicates CD4+ T cells that produce IFN-γ, TNF-α, and interleukin-2 simultaneously. €œBoth Th2” indicates CD4+ T cells that can produce Th2 cytokines interleukin-5 and interleukin-13 at the same time.T-cell responses in 16 participants who were randomly selected from groups A through D, 4 participants per group, showed that adjuvanted regimens induced antigen-specific polyfunctional CD4+ T-cell responses that were reflected in IFN-γ, IL-2, and TNF-α production on spike protein stimulation. A strong bias toward this Th1 phenotype was noted. Th2 responses (as measured by IL-5 and IL-13 cytokines) were minimal (Figure 5).To the Editor.

    Rapid and accurate diagnostic tests are essential for controlling the ongoing Covid-19 pandemic. Although the current standard involves testing of nasopharyngeal swab specimens by quantitative reverse-transcriptase polymerase chain reaction (RT-qPCR) to detect SARS-CoV-2, saliva specimens may be an alternative diagnostic sample.1-4 Rigorous evaluation is needed to determine how saliva specimens compare with nasopharyngeal swab specimens with respect to sensitivity in detection of SARS-CoV-2 during the course of infection. A total of 70 inpatients with Covid-19 provided written informed consent to participate in our study (see the Methods section in Supplementary Appendix 1, available with the full text of this letter at NEJM.org). After Covid-19 was confirmed with a positive nasopharyngeal swab specimen at hospital admission, we obtained additional samples from the patients during hospitalization.

    We tested saliva specimens collected by the patients themselves and nasopharyngeal swabs collected from the patients at the same time point by health care workers. Figure 1. Figure 1. SARS-CoV-2 RNA Titers in Saliva Specimens and Nasopharyngeal Swab Specimens.

    Samples were obtained from 70 hospital inpatients who had a diagnosis of Covid-19. Panel A shows SARS-CoV-2 RNA titers in the first available nasopharyngeal and saliva samples. The lines indicate samples from the same patient. Results were compared with the use of a Wilcoxon signed-rank test (P<0.001).

    Panel B shows percentages of positivity for SARS-CoV-2 in tests of the first matched nasopharyngeal and saliva samples at 1 to 5 days, 6 to 10 days, and 11 or more days (maximum, 53 days) after the diagnosis of Covid-19. Panel C shows longitudinal SARS-CoV-2 RNA copies per milliliter in 97 saliva samples, according to days since symptom onset. Each circle represents a separate sample. Dashed lines indicate additional samples from the same patient.

    The red line indicates a negative saliva sample that was followed by a positive sample at the next collection of a specimen. Panel D shows longitudinal SARS-CoV-2 RNA copies per milliliter in 97 nasopharyngeal swab specimens, according to days since symptom onset. The red lines indicate negative nasopharyngeal swab specimens there were followed by a positive swab at the next collection of a specimen. The gray area in Panels C and D indicates samples that were below the lower limit of detection of 5610 virus RNA copies per milliliter of sample, which is at cycle threshold 38 of our quantitative reverse-transcriptase polymerase chain reaction assay targeting the SARS-CoV-2 N1 sequence recommended by the Centers for Disease Control and Prevention.

    To analyze these data, we used a linear mixed-effects regression model (see Supplementary Appendix 1) that accounts for the correlation between samples collected from the same person at a single time point (i.e., multivariate response) and the correlation between samples collected across time from the same patient (i.e., repeated measures). All the data used to generate this figure, including the raw cycle thresholds, are provided in Supplementary Data 1 in Supplementary Appendix 2.Using primer sequences from the Centers for Disease Control and Prevention, we detected more SARS-CoV-2 RNA copies in the saliva specimens (mean log copies per milliliter, 5.58. 95% confidence interval [CI], 5.09 to 6.07) than in the nasopharyngeal swab specimens (mean log copies per milliliter, 4.93. 95% CI, 4.53 to 5.33) (Figure 1A, and Fig.

    S1 in Supplementary Appendix 1). In addition, a higher percentage of saliva samples than nasopharyngeal swab samples were positive up to 10 days after the Covid-19 diagnosis (Figure 1B). At 1 to 5 days after diagnosis, 81% (95% CI, 71 to 96) of the saliva samples were positive, as compared with 71% (95% CI, 67 to 94) of the nasopharyngeal swab specimens. These findings suggest that saliva specimens and nasopharyngeal swab specimens have at least similar sensitivity in the detection of SARS-CoV-2 during the course of hospitalization.

    Because the results of testing of nasopharyngeal swab specimens to detect SARS-CoV-2 may vary with repeated sampling in individual patients,5 we evaluated viral detection in matched samples over time. The level of SARS-CoV-2 RNA decreased after symptom onset in both saliva specimens (estimated slope, −0.11. 95% credible interval, −0.15 to −0.06) (Figure 1C) and nasopharyngeal swab specimens (estimated slope, −0.09. 95% credible interval, −0.13 to −0.05) (Figure 1D).

    In three instances, a negative nasopharyngeal swab specimen was followed by a positive swab at the next collection of a specimen (Figure 1D). This phenomenon occurred only once with the saliva specimens (Figure 1C). During the clinical course, we observed less variation in levels of SARS-CoV-2 RNA in the saliva specimens (standard deviation, 0.98 virus RNA copies per milliliter. 95% credible interval, 0.08 to 1.98) than in the nasopharyngeal swab specimens (standard deviation, 2.01 virus RNA copies per milliliter.

    95% credible interval, 1.29 to 2.70) (see Supplementary Appendix 1). Recent studies have shown that SARS-CoV-2 can be detected in the saliva of asymptomatic persons and outpatients.1-3 We therefore screened 495 asymptomatic health care workers who provided written informed consent to participate in our prospective study, and we used RT-qPCR to test both saliva and nasopharyngeal samples obtained from these persons. We detected SARS-CoV-2 RNA in saliva specimens obtained from 13 persons who did not report any symptoms at or before the time of sample collection. Of these 13 health care workers, 9 had collected matched nasopharyngeal swab specimens by themselves on the same day, and 7 of these specimens tested negative (Fig.

    S2). The diagnosis in the 13 health care workers with positive saliva specimens was later confirmed in diagnostic testing of additional nasopharyngeal samples by a CLIA (Clinical Laboratory Improvement Amendments of 1988)–certified laboratory. Variation in nasopharyngeal sampling may be an explanation for false negative results, so monitoring an internal control for proper sample collection may provide an alternative evaluation technique. In specimens collected from inpatients by health care workers, we found greater variation in human RNase P cycle threshold (Ct) values in nasopharyngeal swab specimens (standard deviation, 2.89 Ct.

    95% CI, 26.53 to 27.69) than in saliva specimens (standard deviation, 2.49 Ct. 95% CI, 23.35 to 24.35). When health care workers collected their own specimens, we also found greater variation in RNase P Ct values in nasopharyngeal swab specimens (standard deviation, 2.26 Ct. 95% CI, 28.39 to 28.56) than in saliva specimens (standard deviation , 1.65 Ct.

    95% CI, 24.14 to 24.26) (Fig. S3). Collection of saliva samples by patients themselves negates the need for direct interaction between health care workers and patients. This interaction is a source of major testing bottlenecks and presents a risk of nosocomial infection.

    Collection of saliva samples by patients themselves also alleviates demands for supplies of swabs and personal protective equipment. Given the growing need for testing, our findings provide support for the potential of saliva specimens in the diagnosis of SARS-CoV-2 infection. Anne L. Wyllie, Ph.D.Yale School of Public Health, New Haven, CT [email protected]John Fournier, M.D.Yale School of Medicine, New Haven, CTArnau Casanovas-Massana, Ph.D.Yale School of Public Health, New Haven, CTMelissa Campbell, M.D.Maria Tokuyama, Ph.D.Pavithra Vijayakumar, B.A.Yale School of Medicine, New Haven, CTJoshua L.

    Warren, Ph.D.Yale School of Public Health, New Haven, CTBertie Geng, M.D.Yale School of Medicine, New Haven, CTM. Catherine Muenker, M.S.Adam J. Moore, M.P.H.Chantal B.F. Vogels, Ph.D.Mary E.

    Petrone, B.S.Isabel M. Ott, B.S.Yale School of Public Health, New Haven, CTPeiwen Lu, Ph.D.Arvind Venkataraman, B.S.Alice Lu-Culligan, B.S.Jonathan Klein, B.S.Yale School of Medicine, New Haven, CTRebecca Earnest, M.P.H.Yale School of Public Health, New Haven, CTMichael Simonov, M.D.Rupak Datta, M.D., Ph.D.Ryan Handoko, M.D.Nida Naushad, B.S.Lorenzo R. Sewanan, M.Phil.Jordan Valdez, B.S.Yale School of Medicine, New Haven, CTElizabeth B. White, A.B.Sarah Lapidus, M.S.Chaney C.

    Kalinich, M.P.H.Yale School of Public Health, New Haven, CTXiaodong Jiang, M.D., Ph.D.Daniel J. Kim, A.B.Eriko Kudo, Ph.D.Melissa Linehan, M.S.Tianyang Mao, B.S.Miyu Moriyama, Ph.D.Ji E. Oh, M.D., Ph.D.Annsea Park, B.A.Julio Silva, B.S.Eric Song, M.S.Takehiro Takahashi, M.D., Ph.D.Manabu Taura, Ph.D.Orr-El Weizman, B.A.Patrick Wong, M.S.Yexin Yang, B.S.Santos Bermejo, B.S.Yale School of Medicine, New Haven, CTCamila D. Odio, M.D.Yale New Haven Health, New Haven, CTSaad B.

    Omer, M.B., B.S., Ph.D.Yale Institute for Global Health, New Haven, CTCharles S. Dela Cruz, M.D., Ph.D.Shelli Farhadian, M.D., Ph.D.Richard A. Martinello, M.D.Akiko Iwasaki, Ph.D.Yale School of Medicine, New Haven, CTNathan D. Grubaugh, Ph.D.Albert I.

    Ko, M.D.Yale School of Public Health, New Haven, CT [email protected], [email protected] Supported by the Huffman Family Donor Advised Fund, a Fast Grant from Emergent Ventures at the Mercatus Center at George Mason University, the Yale Institute for Global Health, the Yale School of Medicine, a grant (U19 AI08992, to Dr. Ko) from the National Institute of Allergy and Infectious Diseases, the Beatrice Kleinberg Neuwirth Fund, and a grant (Rubicon 019.181EN.004, to Dr. Vogel) from the Dutch Research Council (NWO). Disclosure forms provided by the authors are available with the full text of this letter at NEJM.org.

    This letter was published on August 28, 2020, at NEJM.org. Drs. Grubaugh and Ko contributed equally to this letter. 5 References1.

    Kojima N, Turner F, Slepnev V, et al. Self-collected oral fluid and nasal swabs demonstrate comparable sensitivity to clinician collected nasopharyngeal swabs for Covid-19 detection. April 15, 2020 (https://www.medrxiv.org/content/10.1101/2020.04.11.20062372v1). Preprint.Google Scholar2.

    Williams E, Bond K, Zhang B, Putland M, Williamson DA. Saliva as a non-invasive specimen for detection of SARS-CoV-2. J Clin Microbiol 2020;58(8):e00776-20-e00776-20.3. Pasomsub E, Watcharananan SP, Boonyawat K, et al.

    Saliva sample as a non-invasive specimen for the diagnosis of coronavirus disease 2019. A cross-sectional study. Clin Microbiol Infect 2020 May 15 (Epub ahead of print).4. Vogels CBF, Brackney D, Wang J, et al.

    SalivaDirect. Simple and sensitive molecular diagnostic test for SARS-CoV-2 surveillance. August 4, 2020 (https://www.medrxiv.org/content/10.1101/2020.08.03.20167791v1). Preprint.Google Scholar5.

    Zou L, Ruan F, Huang M, et al. SARS-CoV-2 viral load in upper respiratory specimens of infected patients. N Engl J Med 2020;382:1177-1179.Antibodies are immune proteins that mark the evolution of the host immune response to infection. Antibodies can be measured in a sensitive and specific manner, providing an archive that reflects recent or previous infection.

    If maintained at sufficiently high levels, antibodies can rapidly block infection on reexposure, conferring long-lived protection.Unlike pathogen detection, which is detectable only transiently, at the time of pathogen shedding at sites where diagnostic material is collected, antibodies represent durable markers of infection, providing critical information on infection rates at a population level. Contrary to recent reports suggesting that SARS-CoV-2 RNA testing alone, in the absence of antibodies, will be sufficient to track and contain the pandemic, the cost, complexity, and transient nature of RNA testing for pathogen detection render it an incomplete metric of viral spread at a population level. Instead, the accurate assessment of antibodies during a pandemic can provide important population-based data on pathogen exposure, facilitate an understanding of the role of antibodies in protective immunity, and guide vaccine development.In midsummer 2020, studies emerged pointing to rapid waning of antibody immunity,1,2 with reports across the globe suggesting that antibody responses were inversely correlated to disease severity,4 even suggesting that asymptomatic infection could occur without seroconversion.5 Consistently, in a month-long study, antibody titers were noted to wane both in patients with mild infection and in those with severe infection,2 which raised the possibility that humoral immunity to this coronavirus may be very short-lived.Stefansson and colleagues now report in the Journal their findings on the impact and implications of antibody testing at a population level, capturing insights on prevalence, fatality risk, and durability of immunity.3 The study was performed in Iceland, where 15% of the country’s population was tested for infection with SARS-CoV-2 by quantitative polymerase-chain-reaction (PCR) and antibody testing. The study involved approximately 30,000 persons, including those with hospital, community, and household infections and exposures.

    Sampling of the population was performed in an unbiased manner. Using two highly sensitive and specific assays, Stefansson and colleagues monitored antibody levels and durability over 4 months, whereas previous studies profiled antibody kinetics for only 28 days.2 Kinetic analyses of various antibody isotypes were captured across different SARS-CoV-2 antigens, offering an unprecedented snapshot of seroconversion rates and seromaintenance.Coupling PCR and multi-antigen, multi-isotype antibody surveillance, the study provides an internally validated analysis of the power of serologic testing. From their data, Stefansson and colleagues calculate that approximately 56% of seropositive persons also had a confirmed PCR test, demonstrating that antibody testing captured a larger percentage of exposures. It is notable that nearly a third of the infections were detected in persons with asymptomatic infection.

    This unbiased population-level sampling allowed for the calculation of infection fatality risk at 0.3% in Iceland. Additional observations confirmed elevated antibody levels in older adults and in persons who were hospitalized. Conversely, antibody levels were lower in smokers and in women who had less severe disease.Figure 1. Figure 1.

    Humoral Immune Response. Shown are the kinetics of the humoral immune response after infection, comprising two waves of antibodies. Wave 1 antibodies are produced by rapidly expanding, short-lived plasma cells aimed at populating the systemic circulation with antibodies that provide some level of defense as more affinity-matured antibodies evolve. Wave 2 antibodies are generated by long-lived plasma cells that, although less common, generate potent high-affinity antibodies that typically confer long-lived immunity.

    Because the decay kinetics differ considerably between wave 1 and wave 2 antibodies, sampling time can dramatically affect calculations of the rate of decay. Rapid decay would be observed at the end of wave 1, whereas slower decay would be observed in wave 2.The most striking observation was that antibodies remained stable over the 4 months after diagnosis, a finding captured in a subgroup of longitudinally monitored subjects. Unlike previous studies,2 this study suggested stability of SARS-CoV-2 humoral immunity. Discordant results may simply be attributable to sampling biases.

    Infections and vaccines generate two waves of antibodies. The first wave is generated by early short-lived plasma cells, poised to populate the systemic circulation, but this wave subsides rapidly after resolution of acute infection. The second wave is generated by a smaller number of longer-lived plasma cells that provide long-lived immunity (Figure 1).6 Thus, sampling soon after infection, during wave 1, may point toward a robust though transient waning. Conversely, sampling later or over a longer period of time may provide a more accurate reflection of the decay patterns of the immune response.

    Along these lines, a rise and early decay of antibodies was observed in the Icelandic study, but with limited loss of antibodies at later time points, a finding that points to stable SARS-CoV-2 immunity for at least 4 months after infection.This study focused on a homogeneous population largely from a single ethnic origin and geographic region. Thus, future extended longitudinal studies will be necessary to more accurately define the half-life of SARS-CoV-2 antibodies. That said, this study provides hope that host immunity to this unpredictable and highly contagious virus may not be fleeting and may be similar to that elicited by most other viral infections.Whether antibodies that persist confer protection and retain neutralizing or other protective effector functions that are required to block reinfection remains unclear. Nevertheless, the data reported by Stefansson and colleagues point to the utility of antibody assays as highly cost-effective alternatives to PCR testing for population-level surveillance, which is critical to the safe reopening of cities and schools, and as biomarkers and possible effectors of immunity — useful tools that we can deploy now, while we scan the horizon (and the pages of medical journals) for the wave of vaccines that will end the pandemic of Covid-19.In a laboratory setting, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was inoculated into human bronchial epithelial cells.

    This inoculation, which was performed in a biosafety level 3 facility, had a multiplicity of infection (indicating the ratio of virus particles to targeted airway cells) of 3:1. These cells were then examined 96 hours after infection with the use of scanning electron microscopy. An en face image (Panel A) shows an infected ciliated cell with strands of mucus attached to the cilia tips. At higher magnification, an image (Panel B) shows the structure and density of SARS-CoV-2 virions produced by human airway epithelial cells.

    Virus production was approximately 3×106 plaque-forming units per culture, a finding that is consistent with a high number of virions produced and released per cell.Camille Ehre, Ph.D.Baric and Boucher Laboratories at University of North Carolina School of Medicine, Chapel Hill, NC [email protected].

    Specificity of SARS-CoV-2 Antibody Assays Both assays measuring pan-Ig antibodies had low numbers of buy prozac fluoxetine online false positives among samples collected in 2017. There were 0 and 1 false positives for the two assays among 472 samples, results that compared favorably with those obtained with the single buy prozac fluoxetine online IgM anti-N and IgG anti-N assays (Table S3). Because of the low prevalence of SARS-CoV-2 infection in Iceland, we required positive results from both pan-Ig antibody assays for a sample to be considered seropositive (see Supplementary Methods in Supplementary Appendix 1).

    None of the samples collected in early 2020 group were buy prozac fluoxetine online seropositive, which indicates that the virus had not spread widely in Iceland before February 2020. SARS-CoV-2 Antibodies among qPCR-Positive Persons Figure 2. Figure 2 buy prozac fluoxetine online.

    Antibody Prevalence and Titers among qPCR-Positive Cases buy prozac fluoxetine online as a Function of Time since Diagnosis by qPCR. Shown are the percentages of samples positive for both pan-Ig antibody assays and the antibody titers. Red denotes the count or percentage of samples among persons during their hospitalization (249 samples from 48 persons), and blue buy prozac fluoxetine online denotes the count or percentage of samples among persons after they were declared recovered (1853 samples from 1215 persons).

    Vertical bars denote 95% confidence intervals. The dashed lines indicated the thresholds for buy prozac fluoxetine online a test to be declared positive. OD denotes optical density, and buy prozac fluoxetine online RBD receptor binding domain.Table 1.

    Table 1. Prevalence of buy prozac fluoxetine online SARS-CoV-2 Antibodies by Sample Collection as Measured by Two Pan-Ig Antibody Assays. Twenty-five days after diagnosis by qPCR, more than 90% of samples from recovered persons tested positive with both pan-Ig antibody assays, and the percentage of persons testing positive remained stable thereafter (Figure 2 and Fig.

    S2). Hospitalized persons seroconverted more frequently and quickly after qPCR diagnosis than did nonhospitalized persons (Figure 2 and Fig. S3).

    Of 1215 persons who had recovered (on the basis of results for the most recently obtained sample from persons for whom we had multiple samples), 1107 were seropositive (91.1%. 95% confidence interval [CI], 89.4 to 92.6) (Table 1 and Table S4). Since some diagnoses may have been made on the basis of false positive qPCR results, we determined that 91.1% represents the lower bound of sensitivity of the combined pan-Ig tests for the detection of SARS-CoV-2 antibodies among recovered persons.

    Table 2. Table 2. Results of Repeated Pan-Ig Antibody Tests among Recovered qPCR-Diagnosed Persons.

    Among the 487 recovered persons with two or more samples, 19 (4%) had different pan-Ig antibody test results at different time points (Table 2 and Fig. S4). It is notable that of the 22 persons with an early sample that tested negative for both pan-Ig antibodies, 19 remained negative at the most recent test date (again, for both antibodies).

    One person tested positive for both pan-Ig antibodies in the first test and negative for both in the most recent test. The longitudinal changes in antibody levels among recovered persons were consistent with the cross-sectional results (Fig. S5).

    Antibody levels were higher in the last sample than in the first sample when the antibodies were measured with the two pan-Ig assays, slightly lower than in the first sample when measured with IgG anti-N and IgG anti-S1 assays, and substantially lower than in the first sample when measured with IgM anti-N and IgA anti-S1 assays. IgG anti-N, IgM anti-N, IgG anti-S1, and IgA anti-S1 antibody levels were correlated among the qPCR-positive persons (Figs. S5 and S6 and Table S5).

    Antibody levels measured with both pan-Ig antibody assays increased over the first 2 months after qPCR diagnosis and remained at a plateau over the next 2 months of the study. IgM anti-N antibody levels increased rapidly soon after diagnosis and then fell rapidly and were generally not detected after 2 months. IgA anti-S1 antibodies decreased 1 month after diagnosis and remained detectable thereafter.

    IgG anti-N and anti-S1 antibody levels increased during the first 6 weeks after diagnosis and then decreased slightly. SARS-CoV-2 Infection in Quarantine Table 3. Table 3.

    SARS-CoV-2 Infection among Quarantined Persons According to Exposure Type and Presence of Symptoms. Of the 1797 qPCR-positive Icelanders, 1088 (61%) were in quarantine when SARS-CoV-2 infection was diagnosed by qPCR. We tested for antibodies among 4222 quarantined persons who had not tested qPCR-positive (they had received a negative result by qPCR or had simply not been tested).

    Of those 4222 quarantined persons, 97 (2.3%. 95% CI, 1.9 to 2.8) were seropositive (Table 1). Those with household exposure were 5.2 (95% CI, 3.3 to 8.0) times more likely to be seropositive than those with other types of exposure (Table 3).

    Similarly, a positive result by qPCR for those with household exposure was 5.2 (95% CI, 4.5 to 6.1) times more likely than for those with other types of exposure. When these two sets of results (qPCR-positive and seropositive) were combined, we calculated that 26.6% of quarantined persons with household exposure and 5.0% of quarantined persons without household exposure were infected. Those who had symptoms during quarantine were 3.2 (95% CI, 1.7 to 6.2) times more likely to be seropositive and 18.2 times (95% CI, 14.8 to 22.4) more likely to test positive with qPCR than those without symptoms.

    We also tested persons in two regions of Iceland affected by cluster outbreaks. In a SARS-CoV-2 cluster in Vestfirdir, 1.4% of residents were qPCR-positive and 10% of residents were quarantined. We found that none of the 326 persons outside quarantine who had not been tested by qPCR (or who tested negative) were seropositive.

    In a cluster in Vestmannaeyjar, 2.3% of residents were qPCR-positive and 13% of residents were quarantined. Of the 447 quarantined persons who had not received a qPCR-positive result, 4 were seropositive (0.9%. 95% CI, 0.3 to 2.1).

    Of the 663 outside quarantine in Vestmannaeyjar, 3 were seropositive (0.5%. 95% CI, 0.1 to 0.2%). SARS-CoV-2 Seroprevalence in Iceland None of the serum samples collected from 470 healthy Icelanders between February 18 and March 9, 2020, tested positive for both pan-Ig antibodies, although four were positive for the pan-Ig anti-N assay (0.9%), a finding that suggests that the virus had not spread widely in Iceland before March 9.

    Of the 18,609 persons tested for SARS-CoV-2 antibodies through contact with the Icelandic health care system for reasons other than Covid-19, 39 were positive for both pan-Ig antibody assays (estimated seroprevalence by weighting the sample on the basis of residence, sex, and 10-year age category, 0.3%. 95% CI, 0.2 to 0.4). There were regional differences in the percentages of qPCR-positive persons across Iceland that were roughly proportional to the percentage of people quarantined (Table S6).

    However, after exclusion of the qPCR-positive and quarantined persons, the percentage of persons who tested positive for SARS-CoV-2 antibodies did not correlate with the percentage of those who tested positive by qPCR. The estimated seroprevalence in the random sample collection from Reykjavik (0.4%. 95% CI, 0.3 to 0.6) was similar to that in the Health Care group (0.3%.

    95% CI, 0.2 to 0.4) (Table S6). We calculate that 0.5% of the residents of Iceland have tested positive with qPCR. The 2.3% with SARS-CoV-2 seroconversion among persons in quarantine extrapolates to 0.1% of Icelandic residents.

    On the basis of this finding and the seroprevalence from the Health Care group, we estimate that 0.9% (95% CI, 0.8 to 0.9) of the population of Iceland has been infected by SARS-CoV-2. Approximately 56% of all SARS-CoV-2 infections were therefore diagnosed by qPCR, 14% occurred in quarantine without having been diagnosed with qPCR, and the remaining 30% of infections occurred outside quarantine and were not detected by qPCR. Deaths from Covid-19 in Iceland In Iceland, 10 deaths have been attributed to Covid-19, which corresponds to 3 deaths per 100,000 nationwide.

    Among the qPCR-positive cases, 0.6% (95% CI, 0.3 to 1.0) were fatal. Using the 0.9% prevalence of SARS-CoV-2 infection in Iceland as the denominator, however, we calculate an infection fatality risk of 0.3% (95% CI, 0.2 to 0.6). Stratified by age, the infection fatality risk was substantially lower in those 70 years old or younger (0.1%.

    95% CI, 0.0 to 0.3) than in those over 70 years of age (4.4%. 95% CI, 1.9 to 8.4) (Table S7). Age, Sex, Clinical Characteristics, and Antibody Levels Table 4.

    Table 4. Association of Existing Conditions and Covid-19 Severity with SARS-CoV-2 Antibody Levels among Recovered Persons. SARS-CoV-2 antibody levels were higher in older people and in those who were hospitalized (Table 4, and Table S8 [described in Supplementary Appendix 1 and available in Supplementary Appendix 2]).

    Pan-Ig anti–S1-RBD and IgA anti-S1 levels were lower in female persons. Of the preexisting conditions, and after adjustment for multiple testing, we found that body-mass index, smoking status, and use of antiinflammatory medication were associated with SARS-CoV-2 antibody levels. Body-mass index correlated positively with antibody levels.

    Smokers and users of antiinflammatory medication had lower antibody levels. With respect to clinical characteristics, antibody levels were most strongly associated with hospitalization and clinical severity, followed by clinical symptoms such as fever, maximum temperature reading, cough, and loss of appetite. Severity of these individual symptoms, with the exception of loss of energy, was associated with higher antibody levels.Trial Population Table 1.

    Table 1. Demographic Characteristics of the Participants in the NVX-CoV2373 Trial at Enrollment. The trial was initiated on May 26, 2020.

    134 participants underwent randomization between May 27 and June 6, 2020, including 3 participants who were to serve as backups for sentinel dosing and who immediately withdrew from the trial without being vaccinated (Fig. S1). Of the 131 participants who received injections, 23 received placebo (group A), 25 received 25-μg doses of rSARS-CoV-2 (group B), 29 received 5-μg doses of rSARS-CoV-2 plus Matrix-M1, including three sentinels (group C), 28 received 25-μg doses of rSARS-CoV-2 plus Matrix-M1, including three sentinels (group D), and 26 received a single 25-μg dose of rSARS-CoV-2 plus Matrix-M1 followed by a single dose of placebo (group E).

    All 131 participants received their first vaccination on day 0, and all but 3 received their second vaccination at least 21 days later. Exceptions include 2 in the placebo group (group A) who withdrew consent (unrelated to any adverse event) and 1 in the 25-μg rSARS-CoV-2 + Matrix-M1 group (group D) who had an unsolicited adverse event (mild cellulitis. See below).

    Demographic characteristics of the participants are presented in Table 1. Of note, missing data were infrequent. Safety Outcomes No serious adverse events or adverse events of special interest were reported, and vaccination pause rules were not implemented.

    As noted above, one participant did not receive a second vaccination owing to an unsolicited adverse event, mild cellulitis, that was associated with infection after an intravenous cannula placement to address an unrelated mild adverse event that occurred during the second week of follow-up. Second vaccination was withheld because the participant was still recovering and receiving antibiotics. This participant remains in the trial.

    Figure 2. Figure 2. Solicited Local and Systemic Adverse Events.

    The percentage of participants in each vaccine group (groups A, B, C, D, and E) with adverse events according to the maximum FDA toxicity grade (mild, moderate, or severe) during the 7 days after each vaccination is plotted for solicited local (Panel A) and systemic (Panel B) adverse events. There were no grade 4 (life-threatening) events. Participants who reported 0 events make up the remainder of the 100% calculation (not displayed).

    Excluded were the three sentinel participants in groups C (5 μg + Matrix-M1, 5 μg + Matrix-M1) and D (25 μg + Matrix-M1, 25 μg + Matrix-M1), who received the trial vaccine in an open-label manner (see Table S7 for complete safety data on all participants).Overall reactogenicity was largely absent or mild, and second vaccinations were neither withheld nor delayed due to reactogenicity. After the first vaccination, local and systemic reactogenicity was absent or mild in the majority of participants (local. 100%, 96%, 89%, 84%, and 88% of participants in groups A, B, C, D, and E, respectively.

    Systemic. 91%, 92%, 96%, 68%, and 89%) who were unaware of treatment assignment (Figure 2 and Table S7). Two participants (2%), one each in groups D and E, had severe adverse events (headache, fatigue, and malaise).

    Two participants, one each in groups A and E, had reactogenicity events (fatigue, malaise, and tenderness) that extended 2 days after day 7. After the second vaccination, local and systemic reactogenicity were absent or mild in the majority of participants in the five groups (local. 100%, 100%, 65%, 67%, and 100% of participants, respectively.

    Systemic. 86%, 84%, 73%, 58%, and 96%) who were unaware of treatment assignment. One participant, in group D, had a severe local event (tenderness), and eight participants, one or two participants in each group, had severe systemic events.

    The most common severe systemic events were joint pain and fatigue. Only one participant, in group D, had fever (temperature, 38.1°C) after the second vaccination, on day 1 only. No adverse event extended beyond 7 days after the second vaccination.

    Of note, the mean duration of reactogenicity events was 2 days or less for both the first vaccination and second vaccination periods. Laboratory abnormalities of grade 2 or higher occurred in 13 participants (10%). 9 after the first vaccination and 4 after the second vaccination (Table S8).

    Abnormal laboratory values were not associated with any clinical manifestations and showed no worsening with repeat vaccination. Six participants (5%. Five women and one man) had grade 2 or higher transient reductions in hemoglobin from baseline, with no evidence of hemolysis or microcytic anemia and with resolution within 7 to 21 days.

    Of the six, two had an absolute hemoglobin value (grade 2) that resolved or stabilized during the testing period. Four participants (3%), including one who had received placebo, had elevated liver enzymes that were noted after the first vaccination and resolved within 7 to 14 days (i.e., before the second vaccination). Vital signs remained stable immediately after vaccination and at all visits.

    Unsolicited adverse events (Table S9) were predominantly mild in severity (in 71%, 91%, 83%, 90%, and 82% of participants in groups A, B, C, D, and E, respectively) and were similarly distributed across the groups receiving adjuvanted and unadjuvanted vaccine. There were no reports of severe adverse events. Immunogenicity Outcomes Figure 3.

    Figure 3. SARS-CoV-2 Anti-Spike IgG and Neutralizing Antibody Responses. Shown are geometric mean anti-spike IgG enzyme-linked immunosorbent assay (ELISA) unit responses to recombinant severe acute respiratory syndrome coronavirus 2 (rSARS-CoV-2) protein antigens (Panel A) and wild-type SARS-CoV-2 microneutralization assay at an inhibitory concentration greater than 99% (MN IC>99%) titer responses (Panel B) at baseline (day 0), 3 weeks after the first vaccination (day 21), and 2 weeks after the second vaccination (day 35) for the placebo group (group A), the 25-μg unadjuvanted group (group B), the 5-μg and 25-μg adjuvanted groups (groups C and D, respectively), and the 25-μg adjuvanted and placebo group (group E).

    Diamonds and whisker endpoints represent geometric mean titer values and 95% confidence intervals, respectively. The Covid-19 human convalescent serum panel includes specimens from PCR-confirmed Covid-19 participants, obtained from Baylor College of Medicine (29 specimens for ELISA and 32 specimens for MN IC>99%), with geometric mean titer values according to Covid-19 severity. The severity of Covid-19 is indicated by the colors of the dots for hospitalized patients (including those in intensive care), symptomatic outpatients (with samples collected in the emergency department), and asymptomatic patients who had been exposed to Covid-19 (with samples collected during contact and exposure assessment).

    Mean values (in black) for human convalescent serum are depicted next to (and of same color as) the category of Covid-19 patients, with the overall mean shown above the scatter plot (in black). For each trial vaccine group, the mean at day 35 is depicted above the scatterplot.ELISA anti-spike IgG geometric mean ELISA units (GMEUs) ranged from 105 to 116 at day 0. By day 21, responses had occurred for all adjuvanted regimens (1984, 2626, and 3317 GMEUs for groups C, D, and E, respectively), and geometric mean fold rises (GMFRs) exceeded those induced without adjuvant by a factor of at least 10 (Figure 3 and Table S10).

    Within 7 days after the second vaccination with adjuvant (day 28. Groups C and D), GMEUs had further increased by a factor of 8 (to 15,319 and 20,429, respectively) over responses seen with the first vaccination, and within 14 days (day 35), responses had more than doubled yet again (to 63,160 and 47,521, respectively), achieving GMFRs that were approximately 100 times greater than those observed with rSARS-CoV-2 alone. A single vaccination with adjuvant achieved GMEU levels similar to those in asymptomatic (exposed) patients with Covid-19 (1661), and a second vaccination with adjuvant achieved GMEU levels that exceeded those in convalescent serum from symptomatic outpatients with Covid-19 (7420) by a factor of at least 6 and rose to levels similar to those in convalescent serum from patients hospitalized with Covid-19 (53,391).

    The responses in the two-dose 5-μg and 25-μg adjuvanted vaccine regimens were similar, a finding that highlights the role of adjuvant dose sparing. Neutralizing antibodies were undetectable before vaccination and had patterns of response similar to those of anti-spike antibodies after vaccination with adjuvant (Figure 3 and Table S11). After the first vaccination (day 21), GMFRs were approximately 5 times greater with adjuvant (5.2, 6.3, and 5.9 for groups C, D, and E, respectively) than without adjuvant (1.1).

    By day 35, second vaccinations with adjuvant induced an increase more than 100 times greater (195 and 165 for groups C and D, respectively) than single vaccinations without adjuvant. When compared with convalescent serum, second vaccinations with adjuvant resulted in GMT levels approximately 4 times greater (3906 and 3305 for groups C and D, respectively) than those in symptomatic outpatients with Covid-19 (837) and approached the magnitude of levels observed in hospitalized patients with COVID-19 (7457). At day 35, ELISA anti-spike IgG GMEUs and neutralizing antibodies induced by the two-dose 5-μg and 25-μg adjuvanted vaccine regimens were 4 to 6 times greater than the geometric mean convalescent serum measures (8344 and 983, respectively).

    Figure 4. Figure 4. Correlation of Anti-Spike IgG and Neutralizing Antibody Responses.

    Shown are scatter plots of 100% wild-type neutralizing antibody responses and anti-spike IgG ELISA unit responses at 3 weeks after the first vaccination (day 21) and 2 weeks after the second vaccination (day 35) for the two-dose 25-μg unadjuvanted vaccine (group B. Panel A), the combined two-dose 5-μg and 25-μg adjuvanted vaccine (groups C and D, respectively. Panel B), and convalescent serum from patients with Covid-19 (Panel C).

    In Panel C, the severity of Covid-19 is indicated by the colors of the dots for hospitalized patients (including those in intensive care), symptomatic outpatients (with samples collected in the emergency department), and asymptomatic patients who had been exposed to Covid-19 (with samples collected during contact and exposure assessment).A strong correlation was observed between neutralizing antibody titers and anti-spike IgG GMEUs with adjuvanted vaccine at day 35 (correlation, 0.95) (Figure 4), a finding that was not observed with unadjuvanted vaccine (correlation, 0.76) but was similar to that of convalescent serum (correlation, 0.96). Two-dose regimens of 5-μg and 25-μg rSARS-CoV-2 plus Matrix-M1 produced similar magnitudes of response, and every participant had seroconversion according to either assay measurement. Reverse cumulative-distribution curves for day 35 are presented in Figure S2.

    Figure 5. Figure 5. RSARS-CoV-2 CD4+ T-cell Responses with or without Matrix-M1 Adjuvant.

    Frequencies of antigen-specific CD4+ T cells producing T helper 1 (Th1) cytokines interferon-gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α), and interleukin-2 and for T helper 2 (Th2) cytokines interleukin-5 and interleukin-13 indicated cytokines from four participants each in the placebo (group A), 25-μg unadjuvanted (group B), 5-μg adjuvanted (group C), and 25-μg adjuvanted (group D) groups at baseline (day 0) and 1 week after the second vaccination (day 28) after stimulation with the recombinant spike protein. €œAny 2Th1” indicates CD4+ T cells that can produce two types of Th1 cytokines at the same time. €œAll 3 Th1” indicates CD4+ T cells that produce IFN-γ, TNF-α, and interleukin-2 simultaneously.

    €œBoth Th2” indicates CD4+ T cells that can produce Th2 cytokines interleukin-5 and interleukin-13 at the same time.T-cell responses in 16 participants who were randomly selected from groups A through D, 4 participants per group, showed that adjuvanted regimens induced antigen-specific polyfunctional CD4+ T-cell responses that were reflected in IFN-γ, IL-2, and TNF-α production on spike protein stimulation. A strong bias toward this Th1 phenotype was noted. Th2 responses (as measured by IL-5 and IL-13 cytokines) were minimal (Figure 5).To the Editor.

    Rapid and accurate diagnostic tests are essential for controlling the ongoing Covid-19 pandemic. Although the current standard involves testing of nasopharyngeal swab specimens by quantitative reverse-transcriptase polymerase chain reaction (RT-qPCR) to detect SARS-CoV-2, saliva specimens may be an alternative diagnostic sample.1-4 Rigorous evaluation is needed to determine how saliva specimens compare with nasopharyngeal swab specimens with respect to sensitivity in detection of SARS-CoV-2 during the course of infection. A total of 70 inpatients with Covid-19 provided written informed consent to participate in our study (see the Methods section in Supplementary Appendix 1, available with the full text of this letter at NEJM.org).

    After Covid-19 was confirmed with a positive nasopharyngeal swab specimen at hospital admission, we obtained additional samples from the patients during hospitalization. We tested saliva specimens collected by the patients themselves and nasopharyngeal swabs collected from the patients at the same time point by health care workers. Figure 1.

    Figure 1. SARS-CoV-2 RNA Titers in Saliva Specimens and Nasopharyngeal Swab Specimens. Samples were obtained from 70 hospital inpatients who had a diagnosis of Covid-19.

    Panel A shows SARS-CoV-2 RNA titers in the first available nasopharyngeal and saliva samples. The lines indicate samples from the same patient. Results were compared with the use of a Wilcoxon signed-rank test (P<0.001).

    Panel B shows percentages of positivity for SARS-CoV-2 in tests of the first matched nasopharyngeal and saliva samples at 1 to 5 days, 6 to 10 days, and 11 or more days (maximum, 53 days) after the diagnosis of Covid-19. Panel C shows longitudinal SARS-CoV-2 RNA copies per milliliter in 97 saliva samples, according to days since symptom onset. Each circle represents a separate sample.

    Dashed lines indicate additional samples from the same patient. The red line indicates a negative saliva sample that was followed by a positive sample at the next collection of a specimen. Panel D shows longitudinal SARS-CoV-2 RNA copies per milliliter in 97 nasopharyngeal swab specimens, according to days since symptom onset.

    The red lines indicate negative nasopharyngeal swab specimens there were followed by a positive swab at the next collection of a specimen. The gray area in Panels C and D indicates samples that were below the lower limit of detection of 5610 virus RNA copies per milliliter of sample, which is at cycle threshold 38 of our quantitative reverse-transcriptase polymerase chain reaction assay targeting the SARS-CoV-2 N1 sequence recommended by the Centers for Disease Control and Prevention. To analyze these data, we used a linear mixed-effects regression model (see Supplementary Appendix 1) that accounts for the correlation between samples collected from the same person at a single time point (i.e., multivariate response) and the correlation between samples collected across time from the same patient (i.e., repeated measures).

    All the data used to generate this figure, including the raw cycle thresholds, are provided in Supplementary Data 1 in Supplementary Appendix 2.Using primer sequences from the Centers for Disease Control and Prevention, we detected more SARS-CoV-2 RNA copies in the saliva specimens (mean log copies per milliliter, 5.58. 95% confidence interval [CI], 5.09 to 6.07) than in the nasopharyngeal swab specimens (mean log copies per milliliter, 4.93. 95% CI, 4.53 to 5.33) (Figure 1A, and Fig.

    S1 in Supplementary Appendix 1). In addition, a higher percentage of saliva samples than nasopharyngeal swab samples were positive up to 10 days after the Covid-19 diagnosis (Figure 1B). At 1 to 5 days after diagnosis, 81% (95% CI, 71 to 96) of the saliva samples were positive, as compared with 71% (95% CI, 67 to 94) of the nasopharyngeal swab specimens.

    These findings suggest that saliva specimens and nasopharyngeal swab specimens have at least similar sensitivity in the detection of SARS-CoV-2 during the course of hospitalization. Because the results of testing of nasopharyngeal swab specimens to detect SARS-CoV-2 may vary with repeated sampling in individual patients,5 we evaluated viral detection in matched samples over time. The level of SARS-CoV-2 RNA decreased after symptom onset in both saliva specimens (estimated slope, −0.11.

    95% credible interval, −0.15 to −0.06) (Figure 1C) and nasopharyngeal swab specimens (estimated slope, −0.09. 95% credible interval, −0.13 to −0.05) (Figure 1D). In three instances, a negative nasopharyngeal swab specimen was followed by a positive swab at the next collection of a specimen (Figure 1D).

    This phenomenon occurred only once with the saliva specimens (Figure 1C). During the clinical course, we observed less variation in levels of SARS-CoV-2 RNA in the saliva specimens (standard deviation, 0.98 virus RNA copies per milliliter. 95% credible interval, 0.08 to 1.98) than in the nasopharyngeal swab specimens (standard deviation, 2.01 virus RNA copies per milliliter.

    95% credible interval, 1.29 to 2.70) (see Supplementary Appendix 1). Recent studies have shown that SARS-CoV-2 can be detected in the saliva of asymptomatic persons and outpatients.1-3 We therefore screened 495 asymptomatic health care workers who provided written informed consent to participate in our prospective study, and we used RT-qPCR to test both saliva and nasopharyngeal samples obtained from these persons. We detected SARS-CoV-2 RNA in saliva specimens obtained from 13 persons who did not report any symptoms at or before the time of sample collection.

    Of these 13 health care workers, 9 had collected matched nasopharyngeal swab specimens by themselves on the same day, and 7 of these specimens tested negative (Fig. S2). The diagnosis in the 13 health care workers with positive saliva specimens was later confirmed in diagnostic testing of additional nasopharyngeal samples by a CLIA (Clinical Laboratory Improvement Amendments of 1988)–certified laboratory.

    Variation in nasopharyngeal sampling may be an explanation for false negative results, so monitoring an internal control for proper sample collection may provide an alternative evaluation technique. In specimens collected from inpatients by health care workers, we found greater variation in human RNase P cycle threshold (Ct) values in nasopharyngeal swab specimens (standard deviation, 2.89 Ct. 95% CI, 26.53 to 27.69) than in saliva specimens (standard deviation, 2.49 Ct.

    95% CI, 23.35 to 24.35). When health care workers collected their own specimens, we also found greater variation in RNase P Ct values in nasopharyngeal swab specimens (standard deviation, 2.26 Ct. 95% CI, 28.39 to 28.56) than in saliva specimens (standard deviation , 1.65 Ct.

    95% CI, 24.14 to 24.26) (Fig. S3). Collection of saliva samples by patients themselves negates the need for direct interaction between health care workers and patients.

    This interaction is a source of major testing bottlenecks and presents a risk of nosocomial infection. Collection of saliva samples by patients themselves also alleviates demands for supplies of swabs and personal protective equipment. Given the growing need for testing, our findings provide support for the potential of saliva specimens in the diagnosis of SARS-CoV-2 infection.

    Anne L. Wyllie, Ph.D.Yale School of Public Health, New Haven, CT [email protected]John Fournier, M.D.Yale School of Medicine, New Haven, CTArnau Casanovas-Massana, Ph.D.Yale School of Public Health, New Haven, CTMelissa Campbell, M.D.Maria Tokuyama, Ph.D.Pavithra Vijayakumar, B.A.Yale School of Medicine, New Haven, CTJoshua L. Warren, Ph.D.Yale School of Public Health, New Haven, CTBertie Geng, M.D.Yale School of Medicine, New Haven, CTM.

    Catherine Muenker, M.S.Adam J. Moore, M.P.H.Chantal B.F. Vogels, Ph.D.Mary E.

    Petrone, B.S.Isabel M. Ott, B.S.Yale School of Public Health, New Haven, CTPeiwen Lu, Ph.D.Arvind Venkataraman, B.S.Alice Lu-Culligan, B.S.Jonathan Klein, B.S.Yale School of Medicine, New Haven, CTRebecca Earnest, M.P.H.Yale School of Public Health, New Haven, CTMichael Simonov, M.D.Rupak Datta, M.D., Ph.D.Ryan Handoko, M.D.Nida Naushad, B.S.Lorenzo R. Sewanan, M.Phil.Jordan Valdez, B.S.Yale School of Medicine, New Haven, CTElizabeth B.

    White, A.B.Sarah Lapidus, M.S.Chaney C. Kalinich, M.P.H.Yale School of Public Health, New Haven, CTXiaodong Jiang, M.D., Ph.D.Daniel J. Kim, A.B.Eriko Kudo, Ph.D.Melissa Linehan, M.S.Tianyang Mao, B.S.Miyu Moriyama, Ph.D.Ji E.

    Oh, M.D., Ph.D.Annsea Park, B.A.Julio Silva, B.S.Eric Song, M.S.Takehiro Takahashi, M.D., Ph.D.Manabu Taura, Ph.D.Orr-El Weizman, B.A.Patrick Wong, M.S.Yexin Yang, B.S.Santos Bermejo, B.S.Yale School of Medicine, New Haven, CTCamila D. Odio, M.D.Yale New Haven Health, New Haven, CTSaad B. Omer, M.B., B.S., Ph.D.Yale Institute for Global Health, New Haven, CTCharles S.

    Dela Cruz, M.D., Ph.D.Shelli Farhadian, M.D., Ph.D.Richard A. Martinello, M.D.Akiko Iwasaki, Ph.D.Yale School of Medicine, New Haven, CTNathan D. Grubaugh, Ph.D.Albert I.

    Ko, M.D.Yale School of Public Health, New Haven, CT [email protected], [email protected] Supported by the Huffman Family Donor Advised Fund, a Fast Grant from Emergent Ventures at the Mercatus Center at George Mason University, the Yale Institute for Global Health, the Yale School of Medicine, a grant (U19 AI08992, to Dr. Ko) from the National Institute of Allergy and Infectious Diseases, the Beatrice Kleinberg Neuwirth Fund, and a grant (Rubicon 019.181EN.004, to Dr. Vogel) from the Dutch Research Council (NWO).

    Disclosure forms provided by the authors are available with the full text of this letter at NEJM.org. This letter was published on August 28, 2020, at NEJM.org. Drs.

    Grubaugh and Ko contributed equally to this letter. 5 References1. Kojima N, Turner F, Slepnev V, et al.

    Self-collected oral fluid and nasal swabs demonstrate comparable sensitivity to clinician collected nasopharyngeal swabs for Covid-19 detection. April 15, 2020 (https://www.medrxiv.org/content/10.1101/2020.04.11.20062372v1). Preprint.Google Scholar2.

    Williams E, Bond K, Zhang B, Putland M, Williamson DA. Saliva as a non-invasive specimen for detection of SARS-CoV-2. J Clin Microbiol 2020;58(8):e00776-20-e00776-20.3.

    Pasomsub E, Watcharananan SP, Boonyawat K, et al. Saliva sample as a non-invasive specimen for the diagnosis of coronavirus disease 2019. A cross-sectional study.

    Clin Microbiol Infect 2020 May 15 (Epub ahead of print).4. Vogels CBF, Brackney D, Wang J, et al. SalivaDirect.

    Simple and sensitive molecular diagnostic test for SARS-CoV-2 surveillance. August 4, 2020 (https://www.medrxiv.org/content/10.1101/2020.08.03.20167791v1). Preprint.Google Scholar5.

    Zou L, Ruan F, Huang M, et al. SARS-CoV-2 viral load in upper respiratory specimens of infected patients. N Engl J Med 2020;382:1177-1179.Antibodies are immune proteins that mark the evolution of the host immune response to infection.

    Antibodies can be measured in a sensitive and specific manner, providing an archive that reflects recent or previous infection. If maintained at sufficiently high levels, antibodies can rapidly block infection on reexposure, conferring long-lived protection.Unlike pathogen detection, which is detectable only transiently, at the time of pathogen shedding at sites where diagnostic material is collected, antibodies represent durable markers of infection, providing critical information on infection rates at a population level. Contrary to recent reports suggesting that SARS-CoV-2 RNA testing alone, in the absence of antibodies, will be sufficient to track and contain the pandemic, the cost, complexity, and transient nature of RNA testing for pathogen detection render it an incomplete metric of viral spread at a population level.

    Instead, the accurate assessment of antibodies during a pandemic can provide important population-based data on pathogen exposure, facilitate an understanding of the role of antibodies in protective immunity, and guide vaccine development.In midsummer 2020, studies emerged pointing to rapid waning of antibody immunity,1,2 with reports across the globe suggesting that antibody responses were inversely correlated to disease severity,4 even suggesting that asymptomatic infection could occur without seroconversion.5 Consistently, in a month-long study, antibody titers were noted to wane both in patients with mild infection and in those with severe infection,2 which raised the possibility that humoral immunity to this coronavirus may be very short-lived.Stefansson and colleagues now report in the Journal their findings on the impact and implications of antibody testing at a population level, capturing insights on prevalence, fatality risk, and durability of immunity.3 The study was performed in Iceland, where 15% of the country’s population was tested for infection with SARS-CoV-2 by quantitative polymerase-chain-reaction (PCR) and antibody testing. The study involved approximately 30,000 persons, including those with hospital, community, and household infections and exposures. Sampling of the population was performed in an unbiased manner.

    Using two highly sensitive and specific assays, Stefansson and colleagues monitored antibody levels and durability over 4 months, whereas previous studies profiled antibody kinetics for only 28 days.2 Kinetic analyses of various antibody isotypes were captured across different SARS-CoV-2 antigens, offering an unprecedented snapshot of seroconversion rates and seromaintenance.Coupling PCR and multi-antigen, multi-isotype antibody surveillance, the study provides an internally validated analysis of the power of serologic testing. From their data, Stefansson and colleagues calculate that approximately 56% of seropositive persons also had a confirmed PCR test, demonstrating that antibody testing captured a larger percentage of exposures. It is notable that nearly a third of the infections were detected in persons with asymptomatic infection.

    This unbiased population-level sampling allowed for the calculation of infection fatality risk at 0.3% in Iceland. Additional observations confirmed elevated antibody levels in older adults and in persons who were hospitalized. Conversely, antibody levels were lower in smokers and in women who had less severe disease.Figure 1.

    Figure 1. Humoral Immune Response. Shown are the kinetics of the humoral immune response after infection, comprising two waves of antibodies.

    Wave 1 antibodies are produced by rapidly expanding, short-lived plasma cells aimed at populating the systemic circulation with antibodies that provide some level of defense as more affinity-matured antibodies evolve. Wave 2 antibodies are generated by long-lived plasma cells that, although less common, generate potent high-affinity antibodies that typically confer long-lived immunity. Because the decay kinetics differ considerably between wave 1 and wave 2 antibodies, sampling time can dramatically affect calculations of the rate of decay.

    Rapid decay would be observed at the end of wave 1, whereas slower decay would be observed in wave 2.The most striking observation was that antibodies remained stable over the 4 months after diagnosis, a finding captured in a subgroup of longitudinally monitored subjects. Unlike previous studies,2 this study suggested stability of SARS-CoV-2 humoral immunity. Discordant results may simply be attributable to sampling biases.

    Infections and vaccines generate two waves of antibodies. The first wave is generated by early short-lived plasma cells, poised to populate the systemic circulation, but this wave subsides rapidly after resolution of acute infection. The second wave is generated by a smaller number of longer-lived plasma cells that provide long-lived immunity (Figure 1).6 Thus, sampling soon after infection, during wave 1, may point toward a robust though transient waning.

    Conversely, sampling later or over a longer period of time may provide a more accurate reflection of the decay patterns of the immune response. Along these lines, a rise and early decay of antibodies was observed in the Icelandic study, but with limited loss of antibodies at later time points, a finding that points to stable SARS-CoV-2 immunity for at least 4 months after infection.This study focused on a homogeneous population largely from a single ethnic origin and geographic region. Thus, future extended longitudinal studies will be necessary to more accurately define the half-life of SARS-CoV-2 antibodies.

    That said, this study provides hope that host immunity to this unpredictable and highly contagious virus may not be fleeting and may be similar to that elicited by most other viral infections.Whether antibodies that persist confer protection and retain neutralizing or other protective effector functions that are required to block reinfection remains unclear. Nevertheless, the data reported by Stefansson and colleagues point to the utility of antibody assays as highly cost-effective alternatives to PCR testing for population-level surveillance, which is critical to the safe reopening of cities and schools, and as biomarkers and possible effectors of immunity — useful tools that we can deploy now, while we scan the horizon (and the pages of medical journals) for the wave of vaccines that will end the pandemic of Covid-19.In a laboratory setting, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was inoculated into human bronchial epithelial cells. This inoculation, which was performed in a biosafety level 3 facility, had a multiplicity of infection (indicating the ratio of virus particles to targeted airway cells) of 3:1.

    These cells were then examined 96 hours after infection with the use of scanning electron microscopy. An en face image (Panel A) shows an infected ciliated cell with strands of mucus attached to the cilia tips. At higher magnification, an image (Panel B) shows the structure and density of SARS-CoV-2 virions produced by human airway epithelial cells.

    Virus production was approximately 3×106 plaque-forming units per culture, a finding that is consistent with a high number of virions produced and released per cell.Camille Ehre, Ph.D.Baric and Boucher Laboratories at University of North Carolina School of Medicine, Chapel Hill, NC [email protected].

    Is it safe to take prozac during pregnancy

    €‚For the podcast associated with this article, please visit https://academic.oup.com/eurheartj/pages/Podcasts.This Focus Issue on heart failure (HF) provides novel clinically relevant information on sodium–glucose co-transporter-2 (SGLT2) inhibitors which, initially proposed for the treatment of effects of prozac during pregnancy type 2 diabetes mellitus (T2D), have been found to improve the outcome of HF with is it safe to take prozac during pregnancy reduced ejection fraction (HFrEF) when administered on the top of drugs known to improve the outcome of HF and are recommended in current European Guidelines.1,2Acording to modelling estimates, when compared with no neurohormonal blockade, the use of a broad-based combination of disease-modifying drugs at target doses in patients with HF may reduce the risk of death by as much as 75%. It is surprising that in spite of this powerful therapeutic armamentarium, <1% of patients with chronic HF are currently receiving recommended drugs at doses that have been shown to prolong life.3 The issue opens with a Current Opinion article entitled ‘Totality of evidence in trials of sodium–glucose co-transporter-2 inhibitors in the patients with heart failure with reduced ejection fraction. Implications for clinical practice’ by is it safe to take prozac during pregnancy Milton Packer from the Baylor University Medical Center at Dallas in Texas, USA and colleagues.

    The authors provide a perspective on the totality of evidence with SGLT2 inhibitors in patients with HFrEF.4 This paper is the first to issue a call for a major change in clinical practice based on the concordant results of DAPA-HF and EMPEROR-Reduced trials. The analyses and interpretations that are presented in this manuscript will undoubtedly generate considerable discussion and debate for a long time.Concern about hypotension often leads to withholding of beneficial therapy in patients with HFrEF. In a clinical research manuscript entitled ‘Effect of dapagliflozin is it safe to take prozac during pregnancy according to baseline systolic blood pressure in the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure trial (DAPA-HF)’ John McMurray from the Western Infirmary in Glasgow, UK and colleagues on behalf of the DAPA-HF Investigators and Committees evaluated the efficacy and safety of dapagliflozin according to baseline systolic blood pressure (SBP) in DAPA-HF trial.5 Key inclusion criteria were.

    New York Heart Association (NYHA) class II–IV, left ventricular ejection fraction (LVEF) ≤40%, elevated N-terminal probrain natriuretic peptide (NT-proBNP) level, and SBP ≥95 mmHg. The primary outcome was a composite of worsening HF or cardiovascular death. The efficacy and safety of dapagliflozin was examined using SBP as both is it safe to take prozac during pregnancy a categorical and a continuous variable.

    The placebo-corrected reduction in SBP from baseline to 2 weeks with dapagliflozin was –2.54 mmHg. The benefit and safety is it safe to take prozac during pregnancy of dapagliflozin were consistent across the range of SBP. Study drug discontinuation did not differ between dapagliflozin and placebo across the SBP categories examined.The authors conclude that dapagliflozin had a small effect on SBP in patients with HFrEF and was superior to placebo in improving outcomes, and well tolerated, across the range of SBP included in DAPA-HF.

    The manuscript is accompanied by an Editorial by Francesco Cosentino from the University Hospital Solna in Stockholm, Sweden who comments that altogether, the results of the current post-hoc analysis demonstrating efficacy and safety of dapagliflozin regardless of SBP values might significantly contribute to foster the implementation of dapagliflozin use in HF clinical practice by dissipating any potential safety concern linked with its hypotensive effects.6In a clinical research article entitled ‘A randomized controlled trial of dapagliflozin on left ventricular hypertrophy in people with type two diabetes. The DAPA-LVH trial’, Chim Lang from the University of Dundee in the UK and colleagues tested the hypothesis that dapagliflozin may regress left ventricular hypertrophy (LVH) in people with T2D.7 The authors randomly assigned 66 patients with T2D, LVH, and is it safe to take prozac during pregnancy controlled blood pressure to receive dapagliflozin 10 mg once daily or placebo for 12 months. The primary endpoint was change in absolute left ventricular mass (LVM), assessed by cardiac magnetic resonance imaging (MRI).

    In the intention-to-treat analysis, dapagliflozin significantly reduced LVM compared with placebo, with an absolute mean change of –2.82 g. Additional sensitivity analysis adjusting for baseline is it safe to take prozac during pregnancy LVM, baseline blood pressure, weight, and SBP change showed the LVM change to remain statistically significant. Dapagliflozin significantly reduced pre-specified secondary endpoints including ambulatory 24-h SBP, nocturnal SBP, body weight, visceral adipose tissue, subcutaneous adipose tissue, insulin resistance, and high-sensitivity C-reactive protein.

    Figure 1Column bar charts showing the mean regression of left ventricular mass following dapagliflozin treatment compared to placebo (from Brown AJM, Gandy S, McCrimmon R, Houston JG, Struthers AD, Lang CC. A randomized controlled trial of dapagliflozin on left ventricular hypertrophy in people with is it safe to take prozac during pregnancy type two diabetes. The DAPA-LVH trial.

    See pages 3421–3432).Figure 1Column bar charts showing the mean regression of left ventricular mass following dapagliflozin treatment compared to is it safe to take prozac during pregnancy placebo (from Brown AJM, Gandy S, McCrimmon R, Houston JG, Struthers AD, Lang CC. A randomized controlled trial of dapagliflozin on left ventricular hypertrophy in people with type two diabetes. The DAPA-LVH trial.

    See pages 3421–3432).Lang is it safe to take prozac during pregnancy and colleagues conclude that dapagliflozin treatment significantly reduced LVM in patients with T2D and LVH. The regression of LVM suggests that dapagliflozin can initiate reverse remodelling and changes in left ventricular structure that may partly contribute to cardioprotective effects of dapagliflozin. This manuscript is accompanied by an Editorial by Francesco Paneni from the University of Zurich in Switzerland and colleagues.8 They note that the above-mentioned effects of SGLT2 inhibitors set the ground for a possible beneficial effect of these drugs in patients with HFpEF, where microvascular dysfunction, cardiomyocyte inflammation, and cardiometabolic alterations take centre stage.While several landmark studies have long established that implantable cardioverter-defibrillator (ICD) therapy improves survival for primary prevention of sudden cardiac death ,9 risk stratification parameters and methods for this purpose are clinically underused.

    In a clinical research is it safe to take prozac during pregnancy article entitled ‘Clinical effectiveness of primary prevention implantable cardioverter-defibrillators. Results of the EU-CERT-ICD controlled multicentre cohort study’ Markus Zabel from the Universitätsmedizin Göttingen in Germany and colleagues from the EU-CERT-ICD Study Investigators assessed the current clinical effectiveness of primary prevention by ICD therapy in a prospective investigator-initiated, controlled cohort study, conducted in 44 centres and 15 European countries. The study sought to assess current clinical effectiveness of primary prophylactic ICD is it safe to take prozac during pregnancy implantation.10 The authors recruited 2327 patients with ischaemic or dilated cardiomyopathy and guideline indications for prophylactic ICD implantation.

    The primary endpoint was all-cause mortality. Baseline and follow-up data from 2247 patients were analysable. 1516 patients is it safe to take prozac during pregnancy with first ICD implantation (ICD group) and 731 patients without ICD serving as controls.

    Multivariable models and propensity scoring for adjustment were used to compare the two groups for mortality. Adjusted mortality associated with ICD vs. Control was significantly lower is it safe to take prozac during pregnancy (hazard ratio 0.731).

    Subgroup analyses indicated no ICD benefit in diabetics or in those aged ≥75 years. Figure 2Secondary efficacy endpoints comparing cardiosphere-derived cells and placebo at 6 months. Change in (A) is it safe to take prozac during pregnancy left ventricular end-diastolic volume.

    (B) left ventricular end-systolic volume. And (C) N-terminal pro b-type natriuretic is it safe to take prozac during pregnancy peptide levels. At 6 months.

    CDC, cardiosphere-derived cell. LVEDV, left is it safe to take prozac during pregnancy ventricular end-diastolic volume. LVESV, left ventricular end-systolic volume.

    NT-proBNP, N-terminal pro b-type natriuretic peptide (from Makkar RR, Kereiakes DJ, Aguirre F, Kowalchuk G, Chakravarty T, Malliaras K, Francis GS, Povsic TJ, Schatz R, Traverse JH, Pogoda JM, Smith RR, Marbán L, Ascheim DD, Ostovaneh MR, Lima JAC, DeMaria A, Marbán E, Henry TD. Intracoronary ALLogeneic heart STem cells to is it safe to take prozac during pregnancy Achieve myocardial Regeneration (ALLSTAR). A randomized, placebo-controlled, double-blinded trial.

    See pages 3451--3458).Figure 2Secondary efficacy endpoints comparing cardiosphere-derived cells and placebo at 6 months. Change in is it safe to take prozac during pregnancy (A) left ventricular end-diastolic volume. (B) left ventricular end-systolic volume.

    And (C) N-terminal pro b-type is it safe to take prozac during pregnancy natriuretic peptide levels. At 6 months. CDC, cardiosphere-derived cell.

    LVEDV, left ventricular end-diastolic is it safe to take prozac during pregnancy volume. LVESV, left ventricular end-systolic volume. NT-proBNP, N-terminal pro b-type natriuretic peptide (from Makkar RR, Kereiakes DJ, Aguirre F, Kowalchuk G, Chakravarty T, Malliaras K, Francis GS, Povsic TJ, Schatz R, Traverse JH, Pogoda JM, Smith RR, Marbán L, Ascheim DD, Ostovaneh MR, Lima JAC, DeMaria A, Marbán E, Henry TD.

    Intracoronary ALLogeneic heart is it safe to take prozac during pregnancy STem cells to Achieve myocardial Regeneration (ALLSTAR). A randomized, placebo-controlled, double-blinded trial. See pages 3451--3458).The authors conclude that in contemporary ischaemic/dilated cardiomyopathy patients (LVEF ≤35%, narrow QRS), primary is it safe to take prozac during pregnancy prophylactic ICD treatment was associated with a substantial reduction in mortality, although this improvement was not consistent across the whole population.

    The manuscript is accompanied by an Editorial by N.A. Mark Estes III from the Heart and Vascular Institute UPMC in Pittsburgh, Pennsylvania, USA.11 The authors note that clinicians should be mindful of available risk stratification models and subgroup analyses from the EU-CERT-ICD and other studies. It follows that the process of shared decision-making should include careful consideration of the patient’s wishes and values, with an individualized assessment of potential benefit and risks of primary prevention of sudden death by ICD implantation.Cardiosphere-derived cells (CDCs) are cardiac progenitor cells which exhibit disease-modifying bioactivity in various models of cardiomyopathy and in previous clinical studies of acute myocardial infarction (MI), dilated cardiomyopathy, and Duchenne muscular dystrophy.12,13 In is it safe to take prozac during pregnancy a clinical research article entitled ‘Intracoronary ALLogeneic heart STem cells to Achieve myocardial Regeneration (ALLSTAR).

    A randomized, placebo-controlled, double-blinded trial’, Raj Makkar from the Cedars-Sinai Heart Institute in Los Angeles, California, USA and colleagues assessed the safety and efficacy of intracoronary administration of allogeneic CDCs in the multicentre, randomized, double-blind, placebo-controlled, intracoronary ALLogeneic Heart STem Cells to Achieve Myocardial Regeneration (ALLSTAR) trial.14 The authors enrolled patients 4 weeks to 12 months after MI, with LVEF ≤45% and left ventricular LV scar size ≥15% of LVM by MRI. A pre-specified interim analysis was performed when 6-month MRI data were available. The trial was subsequently stopped due to the low probability of detecting a significant treatment effect of CDCs based on the is it safe to take prozac during pregnancy primary endpoint.

    Patients were randomly allocated in a 2:1 ratio to receive CDCs or placebo in the infarct-related artery by the stop–flow technique. The primary safety endpoint was the occurrence, during 1-month post-intracoronary infusion, of acute myocarditis attributable to allogeneic CDCs, ventricular tachycardia- or ventricular fibrillation-related death, sudden unexpected death, or a major adverse cardiac event (death or hospitalization for HF or non-fatal MI). The primary efficacy endpoint was the relative percentage change in infarct size at 12 months post-infusion as assessed by contrast-enhanced cardiac is it safe to take prozac during pregnancy MRI.

    Makkar and colleagues randomly allocated 90 patients to the CDC group and 44 to the placebo group. The mean baseline LVEF was 40% and is it safe to take prozac during pregnancy the mean scar size was 22% of the LVM. No primary safety endpoint events occurred.

    There was no difference in the percentage change from baseline in scar size between CDC and placebo groups at 6 months. Compared with placebo, there were significant reductions in LV end-diastolic volume, LV end-systolic volume, and NT-proBNP at 6 months in CDC-treated patients.The authors conclude that intracoronary infusion of allogeneic CDCs is it safe to take prozac during pregnancy in patients with post-MI left ventricular dysfunction was safe but did not reduce scar size relative to placebo at 6 months. The manuscript is accompanied by an Editorial by Francisco Fernandez-Aviles from the Hospital General Universitario Gregorio Marañón in Madrid, Spain and colleagues.15 The authors feel that various points need to be better addressed before proceeding again to clinical trials, if we want to move the field of cardiovascular regenerative and reparative medicine forward, for the sake of the cardiovascular health of millions of patients.Treatment of pathological cardiac remodelling and subsequent HF represents an unmet clinical need.

    Long non-coding RNAs (lncRNAs) are emerging as crucial molecular orchestrators of disease processes including that of heart diseases.16,17 In a Basic Science article entitled ‘Targeting muscle-enriched long non-coding RNA H19 reverses pathological cardiac hypertrophy’, Thomas Thum from the Hannover Medical School in Germany, and colleagues report on the powerful therapeutic potential of the conserved lncRNA H19 in the treatment of pathological cardiac hypertrophy.18 Pressure overload-induced left ventricular cardiac remodelling revealed an up-regulation of H19 in the early phase, but a strong sustained repression upon reaching the decompensated phase of HF. The translational potential of H19 was highlighted by its repression in a is it safe to take prozac during pregnancy large animal (pig) model of LVH, in diseased human heart samples, in human stem cell-derived cardiomyocytes, and in human engineered heart tissue in response to afterload enhancement. Pressure overload-induced cardiac hypertrophy in H19 knockout mice was aggravated compared with wild-type mice.

    In contrast, vector-based, cardiomyocyte-directed gene therapy using murine but also human is it safe to take prozac during pregnancy H19 strongly attenuated HF even when cardiac hypertrophy was already established. Mechanistically, using microarray, gene set enrichment analyses, and chromatin immunoprecipitation-DNA sequencing, the authors identified a link between H19 and prohypertrophic nuclear factor of activated T cells (NFAT) signalling. H19 physically interacts with the polycomb repressive complex 2 to suppress H3K27 tri-methylation of the antihypertrophic Tescalcin locus which in turn leads to reduced NFAT expression and activity.Thum and colleagues conclude that H19 is highly conserved and down-regulated in failing hearts from mice, pigs, and humans.

    H19 gene is it safe to take prozac during pregnancy therapy prevents and reverses experimental pressure overload-induced HF. H19 acts as an antihypertrophic lncRNA and represents a promising therapeutic target to combat pathological cardiac remodelling. The manuscript is accompanied by an Editorial by Gianluigi Condorelli from the Humanitas University in Rozzano, Italy and colleagues.

    The authors note that dysregulation of epigenetic mechanisms leading is it safe to take prozac during pregnancy to aberrant loss of cardiomyocyte homeostasis is a critical point to consider in understanding the onset of cardiovascular pathologies. Thus exploiting lncRNAs as therapeutic agents in myocardial disease could pave the way for efficaciously combatting one of the greatest healthcare burdens worldwide.19With the advent of omics, an innovative inductive method has provided researchers with possible ways new to monitor health and disease. This approach incorporates data from studies of the genome, transcriptome, proteome, and metabolome to focus on the assessment of a varied range of biomolecules.20 In a clinical review article entitled ‘Omics phenotyping in heart failure.

    The next frontier’ Antoni Bayes-Genis from the Cardiology Service, Hospital Universitari Germans Trias i Pujol in Badalona, Spain and colleagues provide a state-of-the-art review aiming to provide an up-to-date look at breakthrough omic technologies that are helping to unravel HF disease mechanisms and heterogeneity.21 Genomics, transcriptomics, proteomics, and is it safe to take prozac during pregnancy metabolomics in HF are reviewed in depth. In addition, there is a thorough, expert discussion regarding the value of omics in identifying novel disease pathways, advancing understanding of disease mechanisms, differentiating HF phenotypes, yielding biomarkers for diagnosis or prognosis, or identifying new therapeutic targets in HF. The combination of multiple omics technologies may is it safe to take prozac during pregnancy create a more comprehensive picture of the factors and pathophysiology involved in HF than achieved by either one alone, and provides a rich resource for predictive phenotype modelling.

    However, the successful translation of omics tools as solutions to clinical HF requires that the observations are robust and reproducible, and can be validated across multiple independent populations to ensure confidence in clinical decision-making.This issue is also complemented by a Discussion Forum contribution. In a contribution entitled ‘Heart failure development in obesity. Mechanistic pathways’ Kristjan Karason from the Sahlgrenska University Hospital in Gothenburg, Sweden and colleagues provide a reply to a recent comment entitled ‘Incident heart failure risk after is it safe to take prozac during pregnancy bariatric surgery.

    The role of epicardial fat’.22,23The editors hope that this issue of the European Heart Journal will be of interest to its readers.With thanks to Amelia Meier-Batschelet, Johanna Hugger, and Martin Meyer for help with compilation of this article. References1Docherty KF, Jhund PS, Inzucchi SE, Køber L, Kosiborod MN, Martinez FA, Ponikowski P, DeMets DL, Sabatine MS, Bengtsson O, Sjöstrand M, Langkilde AM, Desai AS, Diez M, Howlett JG, Katova T, Ljungman CEA, O’Meara E, Petrie MC, Schou M, Verma S, Vinh PN, Solomon SD, McMurray JJV. Effects of dapagliflozin in DAPA-HF according to background heart failure therapy is it safe to take prozac during pregnancy.

    Eur Heart J 2020;41:2379–2392.2Ponikowski P, Voors AA,, Anker SD, Bueno H, Cleland JGF, Coats AJS, Falk V, González-Juanatey JR, Harjola VP, Jankowska EA, Jessup M, Linde C, Nihoyannopoulos P, Parissis JT, Pieske B, Riley JP, Rosano GMC, Ruilope LM, Ruschitzka F, Rutten FH, van der Meer P. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) is it safe to take prozac during pregnancy.

    Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart is it safe to take prozac during pregnancy J 2016;37:2129–2200.3Packer M. Are the benefits of SGLT2 inhibitors in heart failure and a reduced ejection fraction influenced by background therapy?.

    Expectations and realities of a new standard of care. Eur Heart J 2020;41:2393–2396.4Butler J, Zannad F, Filippatos G, Anker SD, is it safe to take prozac during pregnancy Packer M. Totality of evidence in trials of sodium–glucose co-transporter-2 inhibitors in the patients with heart failure with reduced ejection fraction.

    Implications for clinical practice. Eur Heart J 2020;41:3398–3401.5Serenelli M, Böhm M, Inzucchi SE, Køber L, Kosiborod MN, Martinez FA, Ponikowski P,, Sabatine MS, Solomon SD, DeMets DL, Bengtsson O, Sjöstrand M, Langkilde AM, Anand IS, Chiang CE, Chopra VK, de is it safe to take prozac during pregnancy Boer RA, Diez M, Dukát A, Ge J, Howlett JG, Katova T, Kitakaze M, Ljungman CEA, Verma S,, Docherty KF, Jhund PS, McMurray JJV. Effect of dapagliflozin according to baseline systolic blood pressure in the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure trial (DAPA-HF).

    Eur Heart J 2020;41:3402–3418.6Savarese G, Cosentino F is it safe to take prozac during pregnancy. The interaction between dapagliflozin and blood pressure in heart failure. New evidence dissipating concerns.

    Eur Heart J 2020;41:3419–3420.7Brown AJM, Gandy S, McCrimmon R, Houston JG, is it safe to take prozac during pregnancy Struthers AD, Lang CC. A randomized controlled trial of dapagliflozin on left ventricular hypertrophy in people with type two diabetes. The DAPA-LVH trial.

    Eur Heart J 2020;41:3421–3432.8Paneni is it safe to take prozac during pregnancy F, Costantino S, Hamdani N. Regression of left ventricular hypertrophy with SGLT2 inhibitors. Eur Heart J 2020;41:3433–3436.9Priori SG, Blomström-Lundqvist C, Mazzanti A, Blom N, Borggrefe M, Camm J, Elliott PM, Fitzsimons D, Hatala R, Hindricks G, Kirchhof P, Kjeldsen K, Kuck KH, Hernandez-Madrid A, Nikolaou N, Norekvål TM, Spaulding C, Van Veldhuisen DJ.

    2015 ESC is it safe to take prozac during pregnancy Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death. The Task Force for the Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death of the European Society of Cardiology (ESC). Endorsed by is it safe to take prozac during pregnancy.

    Association for European Paediatric and Congenital Cardiology (AEPC). Eur Heart J 2015;36:2793–2867.10Zabel M, Willems R, Lubinski A, Bauer A, Brugada J, Conen D, Flevari P, Hasenfuß G, Svetlosak M, Huikuri HV, Malik M, Pavlović N, Schmidt G, Sritharan R, Schlögl S, Szavits-Nossan J, Traykov V, Tuinenburg AE, Willich SN, Harden M, Friede T, Svendsen JH, Sticherling C, Merkely B. Clinical effectiveness of primary prevention is it safe to take prozac during pregnancy implantable cardioverter-defibrillators.

    Results of the EU-CERT-ICD controlled multicentre cohort study. Eur Heart J 2020;41:3437–3447.11Estes MNA, Saba S. Primary prevention of sudden death with the implantable cardioverter defibrillator is it safe to take prozac during pregnancy.

    Bridging the evidence gap. Eur Heart J 2020;41:3448–3450.12Aminzadeh MA, Tseliou E, Sun B, Cheng K, Malliaras K, Makkar RR, Marbán E. Therapeutic efficacy is it safe to take prozac during pregnancy of cardiosphere-derived cells in a transgenic mouse model of non-ischaemic dilated cardiomyopathy.

    Eur Heart J 2015;36:751–762.13Fadini GP, Mehta A, Dhindsa DS, Bonora BM, Sreejit G, Nagareddy P, Quyyumi AA. Circulating stem is it safe to take prozac during pregnancy cells and cardiovascular outcomes. From basic science to the clinic.

    Eur Heart J 2020. Doi:10.1093/eurheartj/ehz923.14Makkar RR, is it safe to take prozac during pregnancy Kereiakes DJ, Aguirre F, Kowalchuk G, Chakravarty T, Malliaras K, Francis GS, Povsic TJ, Schatz R, Traverse JH, Pogoda JM, Smith RR, Marbán L, Ascheim DD, Ostovaneh MR, Lima JAC, DeMaria A, Marbán E, Henry TD. Intracoronary ALLogeneic heart STem cells to Achieve myocardial Regeneration (ALLSTAR).

    A randomized, placebo-controlled, double-blinded trial. Eur Heart is it safe to take prozac during pregnancy J 2020;41:3451–3458.15Sanz-Ruiz R, Fernández-Avilés F. Cardiovascular regenerative and reparative medicine.

    Is myocardial infarction is it safe to take prozac during pregnancy the model?. Eur Heart J 2020;41:3459–3461.16Ounzain S, Micheletti R, Beckmann T, Schroen B, Alexanian M, Pezzuto I, Crippa S, Nemir M, Sarre A, Johnson R, Dauvillier J, Burdet F, Ibberson M, Guigó R, Xenarios I, Heymans S, Pedrazzini T. Genome-wide profiling of the cardiac transcriptome after myocardial infarction identifies novel heart-specific long non-coding RNAs.

    Eur Heart J is it safe to take prozac during pregnancy 2015;36:353–368.17Lüscher TF. Novel molecular mechanisms of vascular disease. Non-coding RNAs, inflammation, and radiation.

    Eur Heart is it safe to take prozac during pregnancy J. 2020;40:2467–2470.18Viereck J, Bührke A, Foinquinos A, Chatterjee S, Kleeberger JA, Xiao K, Janssen-Peters H, Batkai S, Ramanujam D, Kraft T, Cebotari S, Gueler F, Beyer AM, Schmitz J, Bräsen JH, Schmitto JD, Gyöngyösi M, Löser A, Hirt MN, Eschenhagen T, Engelhardt S, Bär C, Thum T. Targeting muscle-enriched long non-coding RNA H19 reverses pathological cardiac hypertrophy.

    Eur Heart is it safe to take prozac during pregnancy J 2020;41:3462–3474.19Pagiatakis C, Hall IF, Condorelli G. Long non-coding RNA H19. A new avenue for RNA is it safe to take prozac during pregnancy therapeutics in cardiac hypertrophy?.

    Eur Heart J 2020;41:3475–3476.20Hoogeveen RM, Pereira JPB, Nurmohamed NS, Zampoleri V, Bom MJ, Baragetti A, Boekholdt SM, Knaapen P, Khaw KT, Wareham NJ, Groen AK, Catapano AL, Koenig W, Levin E, Stroes ESG. Improved cardiovascular risk prediction using targeted plasma proteomics in primary prevention. Eur Heart J is it safe to take prozac during pregnancy 2020;ehaa648.

    21Bayes-Genis A, Liu PP, Lanfear DE, de Boer RA, González A, Thum T, Emdin M, Januzzi JL. Omics phenotyping in heart failure. The next is it safe to take prozac during pregnancy frontier.

    Eur Heart J 2020;41:3477–3484.22Karason K, Jamaly S. Heart failure development in obesity is it safe to take prozac during pregnancy. Mechanistic pathways.

    Eur Heart J 2020;41:3485.23van Woerden G, van Veldhuisen SL, Rienstra M. Incident heart failure risk after is it safe to take prozac during pregnancy bariatric surgery. The role of epicardial fat.

    Eur Heart J 2020;41:1775. Published on behalf of the European is it safe to take prozac during pregnancy Society of Cardiology. All rights reserved.

    © The Author(s) 2020. For permissions, please is it safe to take prozac during pregnancy email. Journals.permissions@oup.com. For the podcast associated with this article, please visit https://academic.oup.com/eurheartj/pages/Podcasts.This Focus Read More Here Issue on heart failure (HF) provides novel clinically relevant information on sodium–glucose co-transporter-2 (SGLT2) inhibitors which, initially proposed for the treatment of type 2 diabetes mellitus (T2D), have been found to improve the outcome of HF with reduced ejection fraction (HFrEF) when administered on the top of drugs known to improve the outcome of HF and are recommended in current European Guidelines.1,2Acording to modelling estimates, when compared with no neurohormonal blockade, the use of a broad-based combination of disease-modifying drugs at target doses in patients with HF may reduce the risk of death by as much as 75%.

    It is surprising that in spite of this powerful therapeutic armamentarium, <1% of patients with chronic is it safe to take prozac during pregnancy HF are currently receiving recommended drugs at doses that have been shown to prolong life.3 The issue opens with a Current Opinion article entitled ‘Totality of evidence in trials of sodium–glucose co-transporter-2 inhibitors in the patients with heart failure with reduced ejection fraction. Implications for clinical practice’ by Milton Packer from the Baylor University Medical Center at Dallas in Texas, USA and colleagues. The authors provide a perspective on the totality of evidence with SGLT2 inhibitors in patients with HFrEF.4 This paper is the first to issue a call for a major change in clinical practice based on the concordant results of DAPA-HF and EMPEROR-Reduced trials.

    The analyses and interpretations that are presented in this manuscript is it safe to take prozac during pregnancy will undoubtedly generate considerable discussion and debate for a long time.Concern about hypotension often leads to withholding of beneficial therapy in patients with HFrEF. In a clinical research manuscript entitled ‘Effect of dapagliflozin according to baseline systolic blood pressure in the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure trial (DAPA-HF)’ John McMurray from the Western Infirmary in Glasgow, UK and colleagues on behalf of the DAPA-HF Investigators and Committees evaluated the efficacy and safety of dapagliflozin according to baseline systolic blood pressure (SBP) in DAPA-HF trial.5 Key inclusion criteria were. New York Heart Association (NYHA) class II–IV, left ventricular ejection fraction (LVEF) ≤40%, elevated N-terminal probrain natriuretic peptide (NT-proBNP) level, and SBP ≥95 mmHg.

    The primary outcome was a composite of worsening HF or cardiovascular is it safe to take prozac during pregnancy death. The efficacy and safety of dapagliflozin was examined using SBP as both a categorical and a continuous variable. The placebo-corrected reduction in SBP from baseline to 2 weeks with dapagliflozin was –2.54 mmHg.

    The benefit and is it safe to take prozac during pregnancy safety of dapagliflozin were consistent across the range of SBP. Study drug discontinuation did not differ between dapagliflozin and placebo across the SBP categories examined.The authors conclude that dapagliflozin had a small effect on SBP in patients with HFrEF and was superior to placebo in improving outcomes, and well tolerated, across the range of SBP included in DAPA-HF. The manuscript is accompanied by an Editorial by Francesco Cosentino from the University Hospital Solna in Stockholm, Sweden who comments that altogether, the results is it safe to take prozac during pregnancy of the current post-hoc analysis demonstrating efficacy and safety of dapagliflozin regardless of SBP values might significantly contribute to foster the implementation of dapagliflozin use in HF clinical practice by dissipating any potential safety concern linked with its hypotensive effects.6In a clinical research article entitled ‘A randomized controlled trial of dapagliflozin on left ventricular hypertrophy in people with type two diabetes.

    The DAPA-LVH trial’, Chim Lang from the University of Dundee in the UK and colleagues tested the hypothesis that dapagliflozin may regress left ventricular hypertrophy (LVH) in people with T2D.7 The authors randomly assigned 66 patients with T2D, LVH, and controlled blood pressure to receive dapagliflozin 10 mg once daily or placebo for 12 months. The primary endpoint was change in absolute left ventricular mass (LVM), assessed by cardiac magnetic resonance imaging (MRI). In the intention-to-treat analysis, dapagliflozin significantly reduced LVM compared with placebo, with an absolute mean change of is it safe to take prozac during pregnancy –2.82 g.

    Additional sensitivity analysis adjusting for baseline LVM, baseline blood pressure, weight, and SBP change showed the LVM change to remain statistically significant. Dapagliflozin significantly reduced pre-specified secondary endpoints including ambulatory 24-h SBP, nocturnal SBP, body weight, visceral adipose tissue, subcutaneous adipose tissue, insulin resistance, and high-sensitivity C-reactive protein. Figure 1Column bar charts showing the mean regression of left ventricular mass following dapagliflozin treatment is it safe to take prozac during pregnancy compared to placebo (from Brown AJM, Gandy S, McCrimmon R, Houston JG, Struthers AD, Lang CC.

    A randomized controlled trial of dapagliflozin on left ventricular hypertrophy in people with type two diabetes. The DAPA-LVH is it safe to take prozac during pregnancy trial. See pages 3421–3432).Figure 1Column bar charts showing the mean regression of left ventricular mass following dapagliflozin treatment compared to placebo (from Brown AJM, Gandy S, McCrimmon R, Houston JG, Struthers AD, Lang CC.

    A randomized controlled trial of dapagliflozin on left ventricular hypertrophy in people with type two diabetes. The DAPA-LVH is it safe to take prozac during pregnancy trial. See pages 3421–3432).Lang and colleagues conclude that dapagliflozin treatment significantly reduced LVM in patients with T2D and LVH.

    The regression of LVM suggests that dapagliflozin can initiate reverse remodelling and changes in left ventricular structure that may partly contribute to cardioprotective effects of dapagliflozin. This manuscript is accompanied by an Editorial by Francesco Paneni from the University of Zurich in Switzerland and colleagues.8 They note that the above-mentioned effects of SGLT2 inhibitors set the ground for a possible beneficial effect of these drugs is it safe to take prozac during pregnancy in patients with HFpEF, where microvascular dysfunction, cardiomyocyte inflammation, and cardiometabolic alterations take centre stage.While several landmark studies have long established that implantable cardioverter-defibrillator (ICD) therapy improves survival for primary prevention of sudden cardiac death ,9 risk stratification parameters and methods for this purpose are clinically underused. In a clinical research article entitled ‘Clinical effectiveness of primary prevention implantable cardioverter-defibrillators.

    Results of the EU-CERT-ICD controlled multicentre cohort study’ Markus Zabel from the Universitätsmedizin Göttingen in Germany and colleagues from the EU-CERT-ICD Study Investigators assessed the current clinical effectiveness of primary prevention by ICD therapy in a prospective investigator-initiated, controlled cohort study, conducted in 44 centres and 15 European countries. The study sought to assess current clinical effectiveness of primary prophylactic ICD implantation.10 The authors recruited 2327 patients with ischaemic or dilated cardiomyopathy is it safe to take prozac during pregnancy and guideline indications for prophylactic ICD implantation. The primary endpoint was all-cause mortality.

    Baseline and follow-up data from 2247 patients were is it safe to take prozac during pregnancy analysable. 1516 patients with first ICD implantation (ICD group) and 731 patients without ICD serving as controls. Multivariable models and propensity scoring for adjustment were used to compare the two groups for mortality.

    Adjusted mortality associated is it safe to take prozac during pregnancy with ICD vs. Control was significantly lower (hazard ratio 0.731). Subgroup analyses indicated no ICD benefit in diabetics or in those aged ≥75 years.

    Figure 2Secondary efficacy endpoints comparing is it safe to take prozac during pregnancy cardiosphere-derived cells and placebo at 6 months. Change in (A) left ventricular end-diastolic volume. (B) left ventricular is it safe to take prozac during pregnancy end-systolic volume.

    And (C) N-terminal pro b-type natriuretic peptide levels. At 6 months. CDC, cardiosphere-derived is it safe to take prozac during pregnancy cell.

    LVEDV, left ventricular end-diastolic volume. LVESV, left ventricular end-systolic volume. NT-proBNP, N-terminal pro b-type natriuretic peptide (from Makkar RR, Kereiakes DJ, Aguirre F, Kowalchuk G, Chakravarty T, Malliaras is it safe to take prozac during pregnancy K, Francis GS, Povsic TJ, Schatz R, Traverse JH, Pogoda JM, Smith RR, Marbán L, Ascheim DD, Ostovaneh MR, Lima JAC, DeMaria A, Marbán E, Henry TD.

    Intracoronary ALLogeneic heart STem cells to Achieve myocardial Regeneration (ALLSTAR). A randomized, placebo-controlled, double-blinded trial. See pages 3451--3458).Figure 2Secondary efficacy endpoints comparing cardiosphere-derived cells and placebo at is it safe to take prozac during pregnancy 6 months.

    Change in (A) left ventricular end-diastolic volume. (B) left ventricular is it safe to take prozac during pregnancy end-systolic volume. And (C) N-terminal pro b-type natriuretic peptide levels.

    At 6 months. CDC, cardiosphere-derived is it safe to take prozac during pregnancy cell. LVEDV, left ventricular end-diastolic volume.

    LVESV, left ventricular end-systolic volume. NT-proBNP, N-terminal pro b-type natriuretic peptide (from Makkar RR, Kereiakes DJ, Aguirre F, Kowalchuk G, Chakravarty T, Malliaras is it safe to take prozac during pregnancy K, Francis GS, Povsic TJ, Schatz R, Traverse JH, Pogoda JM, Smith RR, Marbán L, Ascheim DD, Ostovaneh MR, Lima JAC, DeMaria A, Marbán E, Henry TD. Intracoronary ALLogeneic heart STem cells to Achieve myocardial Regeneration (ALLSTAR).

    A randomized, placebo-controlled, double-blinded trial. See pages 3451--3458).The authors conclude that in contemporary ischaemic/dilated cardiomyopathy patients (LVEF ≤35%, narrow QRS), primary prophylactic ICD treatment was associated with a substantial reduction in mortality, although this improvement was not consistent is it safe to take prozac during pregnancy across the whole population. The manuscript is accompanied by an Editorial by N.A.

    Mark Estes III from the Heart and Vascular Institute UPMC in Pittsburgh, Pennsylvania, USA.11 The authors note that clinicians should be mindful is it safe to take prozac during pregnancy of available risk stratification models and subgroup analyses from the EU-CERT-ICD and other studies. It follows that the process of shared decision-making should include careful consideration of the patient’s wishes and values, with an individualized assessment of potential benefit and risks of primary prevention of sudden death by ICD implantation.Cardiosphere-derived cells (CDCs) are cardiac progenitor cells which exhibit disease-modifying bioactivity in various models of cardiomyopathy and in previous clinical studies of acute myocardial infarction (MI), dilated cardiomyopathy, and Duchenne muscular dystrophy.12,13 In a clinical research article entitled ‘Intracoronary ALLogeneic heart STem cells to Achieve myocardial Regeneration (ALLSTAR). A randomized, placebo-controlled, double-blinded trial’, Raj Makkar from the Cedars-Sinai Heart Institute in Los Angeles, California, USA and colleagues assessed the safety and efficacy of intracoronary administration of allogeneic CDCs in the multicentre, randomized, double-blind, placebo-controlled, intracoronary ALLogeneic Heart STem Cells to Achieve Myocardial Regeneration (ALLSTAR) trial.14 The authors enrolled patients 4 weeks to 12 months after MI, with LVEF ≤45% and left ventricular LV scar size ≥15% of LVM by MRI.

    A pre-specified interim analysis was performed when 6-month is it safe to take prozac during pregnancy MRI data were available. The trial was subsequently stopped due to the low probability of detecting a significant treatment effect of CDCs based on the primary endpoint. Patients were randomly allocated in a 2:1 ratio to receive CDCs or placebo in the infarct-related artery by the stop–flow technique.

    The primary safety endpoint was the occurrence, during 1-month post-intracoronary infusion, of acute myocarditis attributable to allogeneic is it safe to take prozac during pregnancy CDCs, ventricular tachycardia- or ventricular fibrillation-related death, sudden unexpected death, or a major adverse cardiac event (death or hospitalization for HF or non-fatal MI). The primary efficacy endpoint was the relative percentage change in infarct size at 12 months post-infusion as assessed by contrast-enhanced cardiac MRI. Makkar and colleagues randomly allocated 90 is it safe to take prozac during pregnancy patients to the CDC group and 44 to the placebo group.

    The mean baseline LVEF was 40% and the mean scar size was 22% of the LVM. No primary safety endpoint events occurred. There was no is it safe to take prozac during pregnancy difference in the percentage change from baseline in scar size between CDC and placebo groups at 6 months.

    Compared with placebo, there were significant reductions in LV end-diastolic volume, LV end-systolic volume, and NT-proBNP at 6 months in CDC-treated patients.The authors conclude that intracoronary infusion of allogeneic CDCs in patients with post-MI left ventricular dysfunction was safe but did not reduce scar size relative to placebo at 6 months. The manuscript is accompanied by an Editorial by Francisco Fernandez-Aviles from the Hospital General Universitario Gregorio Marañón in Madrid, Spain and colleagues.15 The authors feel that various points need to be better addressed before proceeding again to clinical trials, if we want to move the field of cardiovascular regenerative and reparative medicine forward, for the sake of the cardiovascular health of millions of patients.Treatment of pathological cardiac remodelling and subsequent HF represents an unmet clinical need. Long non-coding RNAs (lncRNAs) are emerging as crucial molecular orchestrators of disease processes including that of heart diseases.16,17 In a Basic is it safe to take prozac during pregnancy Science article entitled ‘Targeting muscle-enriched long non-coding RNA H19 reverses pathological cardiac hypertrophy’, Thomas Thum from the Hannover Medical School in Germany, and colleagues report on the powerful therapeutic potential of the conserved lncRNA H19 in the treatment of pathological cardiac hypertrophy.18 Pressure overload-induced left ventricular cardiac remodelling revealed an up-regulation of H19 in the early phase, but a strong sustained repression upon reaching the decompensated phase of HF.

    The translational potential of H19 was highlighted by its repression in a large animal (pig) model of LVH, in diseased human heart samples, in human stem cell-derived cardiomyocytes, and in human engineered heart tissue in response to afterload enhancement. Pressure overload-induced cardiac hypertrophy in H19 knockout mice was aggravated compared with wild-type mice. In contrast, vector-based, cardiomyocyte-directed gene therapy using murine but also human H19 strongly attenuated HF even when cardiac hypertrophy was already established is it safe to take prozac during pregnancy.

    Mechanistically, using microarray, gene set enrichment analyses, and chromatin immunoprecipitation-DNA sequencing, the authors identified a link between H19 and prohypertrophic nuclear factor of activated T cells (NFAT) signalling. H19 physically interacts with the polycomb repressive complex 2 to suppress H3K27 tri-methylation of the antihypertrophic Tescalcin locus which in turn leads to reduced NFAT expression and activity.Thum and colleagues conclude that H19 is is it safe to take prozac during pregnancy highly conserved and down-regulated in failing hearts from mice, pigs, and humans. H19 gene therapy prevents and reverses experimental pressure overload-induced HF.

    H19 acts as an antihypertrophic lncRNA and represents a promising therapeutic target to combat pathological cardiac remodelling. The manuscript is accompanied by an Editorial by Gianluigi Condorelli from the Humanitas University in Rozzano, Italy and is it safe to take prozac during pregnancy colleagues. The authors note that dysregulation of epigenetic mechanisms leading to aberrant loss of cardiomyocyte homeostasis is a critical point to consider in understanding the onset of cardiovascular pathologies.

    Thus exploiting lncRNAs as therapeutic agents in myocardial disease could pave the way for efficaciously combatting one of the greatest healthcare burdens worldwide.19With the advent of omics, an innovative inductive method has provided researchers with possible ways new to monitor health and disease. This approach incorporates data from studies of the is it safe to take prozac during pregnancy genome, transcriptome, proteome, and metabolome to focus on the assessment of a varied range of biomolecules.20 In a clinical review article entitled ‘Omics phenotyping in heart failure. The next frontier’ Antoni Bayes-Genis from the Cardiology Service, Hospital Universitari Germans Trias i Pujol in Badalona, Spain and colleagues provide a state-of-the-art review aiming to provide an up-to-date look at breakthrough omic technologies that are helping to unravel HF disease mechanisms and heterogeneity.21 Genomics, transcriptomics, proteomics, and metabolomics in HF are reviewed in depth.

    In addition, there is a thorough, expert discussion regarding the value of omics in identifying novel disease pathways, advancing understanding of disease mechanisms, differentiating HF phenotypes, yielding biomarkers for diagnosis or prognosis, or identifying new therapeutic targets in HF. The combination is it safe to take prozac during pregnancy of multiple omics technologies may create a more comprehensive picture of the factors and pathophysiology involved in HF than achieved by either one alone, and provides a rich resource for predictive phenotype modelling. However, the successful translation of omics tools as solutions to clinical HF requires that the observations are robust and reproducible, and can be validated across multiple independent populations to ensure confidence in clinical decision-making.This issue is also complemented by a Discussion Forum contribution.

    In a contribution entitled ‘Heart failure development in is it safe to take prozac during pregnancy obesity. Mechanistic pathways’ Kristjan Karason from the Sahlgrenska University Hospital in Gothenburg, Sweden and colleagues provide a reply to a recent comment entitled ‘Incident heart failure risk after bariatric surgery. The role of epicardial fat’.22,23The editors hope that this issue of the European Heart Journal will be of interest to its readers.With thanks to Amelia Meier-Batschelet, Johanna Hugger, and Martin Meyer for help with compilation of this article.

    References1Docherty KF, Jhund PS, Inzucchi SE, Køber L, Kosiborod MN, Martinez FA, Ponikowski P, DeMets DL, Sabatine MS, Bengtsson is it safe to take prozac during pregnancy O, Sjöstrand M, Langkilde AM, Desai AS, Diez M, Howlett JG, Katova T, Ljungman CEA, O’Meara E, Petrie MC, Schou M, Verma S, Vinh PN, Solomon SD, McMurray JJV. Effects of dapagliflozin in DAPA-HF according to background heart failure therapy. Eur Heart J 2020;41:2379–2392.2Ponikowski P, Voors AA,, Anker SD, Bueno H, Cleland JGF, Coats AJS, Falk V, González-Juanatey JR, Harjola VP, Jankowska EA, Jessup M, Linde C, Nihoyannopoulos P, Parissis JT, Pieske B, Riley JP, Rosano GMC, Ruilope LM, Ruschitzka F, Rutten FH, van der Meer P.

    2016 ESC Guidelines for the is it safe to take prozac during pregnancy diagnosis and treatment of acute and chronic heart failure. The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association is it safe to take prozac during pregnancy (HFA) of the ESC.

    Eur Heart J 2016;37:2129–2200.3Packer M. Are the benefits of SGLT2 inhibitors in heart failure and a reduced ejection fraction influenced by background therapy?. Expectations and realities of a new standard of is it safe to take prozac during pregnancy care.

    Eur Heart J 2020;41:2393–2396.4Butler J, Zannad F, Filippatos G, Anker SD, Packer M. Totality of evidence in trials of sodium–glucose co-transporter-2 inhibitors in the patients with heart failure with reduced ejection fraction. Implications for is it safe to take prozac during pregnancy clinical practice.

    Eur Heart J 2020;41:3398–3401.5Serenelli M, Böhm M, Inzucchi SE, Køber L, Kosiborod MN, Martinez FA, Ponikowski P,, Sabatine MS, Solomon SD, DeMets DL, Bengtsson O, Sjöstrand M, Langkilde AM, Anand IS, Chiang CE, Chopra VK, de Boer RA, Diez M, Dukát A, Ge J, Howlett JG, Katova T, Kitakaze M, Ljungman CEA, Verma S,, Docherty KF, Jhund PS, McMurray JJV. Effect of dapagliflozin according to baseline systolic blood pressure in the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure trial (DAPA-HF). Eur Heart is it safe to take prozac during pregnancy J 2020;41:3402–3418.6Savarese G, Cosentino F.

    The interaction between dapagliflozin and blood pressure in heart failure. New evidence is it safe to take prozac during pregnancy dissipating concerns. Eur Heart J 2020;41:3419–3420.7Brown AJM, Gandy S, McCrimmon R, Houston JG, Struthers AD, Lang CC.

    A randomized controlled trial of dapagliflozin on left ventricular hypertrophy in people with type two diabetes. The DAPA-LVH is it safe to take prozac during pregnancy trial. Eur Heart J 2020;41:3421–3432.8Paneni F, Costantino S, Hamdani N.

    Regression of left ventricular hypertrophy with SGLT2 inhibitors. Eur Heart J 2020;41:3433–3436.9Priori SG, Blomström-Lundqvist C, Mazzanti A, Blom N, Borggrefe M, Camm J, Elliott PM, Fitzsimons D, Hatala R, Hindricks G, Kirchhof P, Kjeldsen K, Kuck KH, Hernandez-Madrid A, Nikolaou N, Norekvål TM, Spaulding C, Van Veldhuisen DJ is it safe to take prozac during pregnancy. 2015 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death.

    The Task Force for the Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death of the is it safe to take prozac during pregnancy European Society of Cardiology (ESC). Endorsed by. Association for European Paediatric and Congenital Cardiology (AEPC).

    Eur Heart J 2015;36:2793–2867.10Zabel M, Willems R, Lubinski A, Bauer A, Brugada J, Conen D, Flevari P, Hasenfuß G, Svetlosak M, Huikuri HV, Malik M, Pavlović is it safe to take prozac during pregnancy N, Schmidt G, Sritharan R, Schlögl S, Szavits-Nossan J, Traykov V, Tuinenburg AE, Willich SN, Harden M, Friede T, Svendsen JH, Sticherling C, Merkely B. Clinical effectiveness of primary prevention implantable cardioverter-defibrillators. Results of the EU-CERT-ICD controlled multicentre cohort study.

    Eur Heart J 2020;41:3437–3447.11Estes is it safe to take prozac during pregnancy MNA, Saba S. Primary prevention of sudden death with the implantable cardioverter defibrillator. Bridging the evidence gap.

    Eur Heart J 2020;41:3448–3450.12Aminzadeh is it safe to take prozac during pregnancy MA, Tseliou E, Sun B, Cheng K, Malliaras K, Makkar RR, Marbán E. Therapeutic efficacy of cardiosphere-derived cells in a transgenic mouse model of non-ischaemic dilated cardiomyopathy. Eur Heart J 2015;36:751–762.13Fadini GP, Mehta A, Dhindsa DS, Bonora BM, Sreejit G, Nagareddy P, is it safe to take prozac during pregnancy Quyyumi AA.

    Circulating stem cells and cardiovascular outcomes. From basic science to the clinic. Eur Heart is it safe to take prozac during pregnancy J 2020.

    Doi:10.1093/eurheartj/ehz923.14Makkar RR, Kereiakes DJ, Aguirre F, Kowalchuk G, Chakravarty T, Malliaras K, Francis GS, Povsic TJ, Schatz R, Traverse JH, Pogoda JM, Smith RR, Marbán L, Ascheim DD, Ostovaneh MR, Lima JAC, DeMaria A, Marbán E, Henry TD. Intracoronary ALLogeneic heart STem cells to Achieve myocardial Regeneration (ALLSTAR). A randomized, placebo-controlled, double-blinded is it safe to take prozac during pregnancy trial.

    Eur Heart J 2020;41:3451–3458.15Sanz-Ruiz R, Fernández-Avilés F. Cardiovascular regenerative and reparative medicine. Is myocardial is it safe to take prozac during pregnancy infarction the model?.

    Eur Heart J 2020;41:3459–3461.16Ounzain S, Micheletti R, Beckmann T, Schroen B, Alexanian M, Pezzuto I, Crippa S, Nemir M, Sarre A, Johnson R, Dauvillier J, Burdet F, Ibberson M, Guigó R, Xenarios I, Heymans S, Pedrazzini T. Genome-wide profiling of the cardiac transcriptome after myocardial infarction identifies novel heart-specific is it safe to take prozac during pregnancy long non-coding RNAs. Eur Heart J 2015;36:353–368.17Lüscher TF.

    Novel molecular mechanisms of vascular disease. Non-coding RNAs, inflammation, is it safe to take prozac during pregnancy and radiation. Eur Heart J.

    2020;40:2467–2470.18Viereck J, Bührke A, Foinquinos A, Chatterjee S, Kleeberger JA, Xiao K, Janssen-Peters H, Batkai S, Ramanujam D, Kraft T, Cebotari S, Gueler F, Beyer AM, Schmitz J, Bräsen JH, Schmitto JD, Gyöngyösi M, Löser A, Hirt MN, Eschenhagen T, Engelhardt S, Bär C, Thum T. Targeting muscle-enriched is it safe to take prozac during pregnancy long non-coding RNA H19 reverses pathological cardiac hypertrophy. Eur Heart J 2020;41:3462–3474.19Pagiatakis C, Hall IF, Condorelli G.

    Long non-coding is it safe to take prozac during pregnancy RNA H19. A new avenue for RNA therapeutics in cardiac hypertrophy?. Eur Heart J 2020;41:3475–3476.20Hoogeveen RM, Pereira JPB, Nurmohamed NS, Zampoleri V, Bom MJ, Baragetti A, Boekholdt SM, Knaapen P, Khaw KT, Wareham NJ, Groen AK, Catapano AL, Koenig W, Levin E, Stroes ESG.

    Improved cardiovascular risk prediction using targeted plasma proteomics in primary is it safe to take prozac during pregnancy prevention. Eur Heart J 2020;ehaa648. 21Bayes-Genis A, Liu PP, Lanfear DE, de Boer RA, González A, Thum T, Emdin M, Januzzi JL.

    Omics phenotyping is it safe to take prozac during pregnancy in heart failure. The next frontier. Eur Heart J 2020;41:3477–3484.22Karason K, Jamaly S.

    Heart failure development is it safe to take prozac during pregnancy in obesity. Mechanistic pathways. Eur Heart is it safe to take prozac during pregnancy J 2020;41:3485.23van Woerden G, van Veldhuisen SL, Rienstra M.

    Incident heart failure risk after bariatric surgery. The role of epicardial fat. Eur Heart is it safe to take prozac during pregnancy J 2020;41:1775.

    Published on behalf of the European Society of Cardiology. All rights reserved. © The is it safe to take prozac during pregnancy Author(s) 2020.

    For permissions, please email. Journals.permissions@oup.com..

    €‚For the podcast associated with this article, please visit https://academic.oup.com/eurheartj/pages/Podcasts.This Focus Issue on heart failure (HF) provides novel clinically relevant information on sodium–glucose co-transporter-2 (SGLT2) inhibitors which, initially proposed for the treatment of type 2 diabetes mellitus (T2D), have been found to improve the outcome of HF with reduced ejection fraction (HFrEF) what happens if you snort prozac when administered on the top of drugs known to improve the outcome of HF and are recommended in current European Guidelines.1,2Acording to modelling estimates, when compared with no neurohormonal blockade, the use of a broad-based buy prozac fluoxetine online combination of disease-modifying drugs at target doses in patients with HF may reduce the risk of death by as much as 75%. It is surprising that in spite of this powerful therapeutic armamentarium, <1% of patients with chronic HF are currently receiving recommended drugs at doses that have been shown to prolong life.3 The issue opens with a Current Opinion article entitled ‘Totality of evidence in trials of sodium–glucose co-transporter-2 inhibitors in the patients with heart failure with reduced ejection fraction. Implications for clinical practice’ by Milton Packer from the Baylor University Medical Center at Dallas in buy prozac fluoxetine online Texas, USA and colleagues. The authors provide a perspective on the totality of evidence with SGLT2 inhibitors in patients with HFrEF.4 This paper is the first to issue a call for a major change in clinical practice based on the concordant results of DAPA-HF and EMPEROR-Reduced trials.

    The analyses and interpretations that are presented in this manuscript will undoubtedly generate considerable discussion and debate for a long time.Concern about hypotension often leads to withholding of beneficial therapy in patients with HFrEF. In a clinical research manuscript entitled ‘Effect of dapagliflozin according to baseline systolic blood pressure in the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure trial (DAPA-HF)’ John McMurray from the Western Infirmary in Glasgow, UK and colleagues on behalf of the DAPA-HF Investigators and Committees evaluated the efficacy and safety of dapagliflozin according to baseline systolic blood buy prozac fluoxetine online pressure (SBP) in DAPA-HF trial.5 Key inclusion criteria were. New York Heart Association (NYHA) class II–IV, left ventricular ejection fraction (LVEF) ≤40%, elevated N-terminal probrain natriuretic peptide (NT-proBNP) level, and SBP ≥95 mmHg. The primary outcome was a composite of worsening HF or cardiovascular death.

    The efficacy and safety of dapagliflozin was examined buy prozac fluoxetine online using SBP as both a categorical and a continuous variable. The placebo-corrected reduction in SBP from baseline to 2 weeks with dapagliflozin was –2.54 mmHg. The benefit and safety of dapagliflozin were buy prozac fluoxetine online consistent across the range of SBP. Study drug discontinuation did not differ between dapagliflozin and placebo across the SBP categories examined.The authors conclude that dapagliflozin had a small effect on SBP in patients with HFrEF and was superior to placebo in improving outcomes, and well tolerated, across the range of SBP included in DAPA-HF.

    The manuscript is accompanied by an Editorial by Francesco Cosentino from the University Hospital Solna in Stockholm, Sweden who comments that altogether, the results of the current post-hoc analysis demonstrating efficacy and safety of dapagliflozin regardless of SBP values might significantly contribute to foster the implementation of dapagliflozin use in HF clinical practice by dissipating any potential safety concern linked with its hypotensive effects.6In a clinical research article entitled ‘A randomized controlled trial of dapagliflozin on left ventricular hypertrophy in people with type two diabetes. The DAPA-LVH trial’, Chim Lang from the University of Dundee in the buy prozac fluoxetine online UK and colleagues tested the hypothesis that dapagliflozin may regress left ventricular hypertrophy (LVH) in people with T2D.7 The authors randomly assigned 66 patients with T2D, LVH, and controlled blood pressure to receive dapagliflozin 10 mg once daily or placebo for 12 months. The primary endpoint was change in absolute left ventricular mass (LVM), assessed by cardiac magnetic resonance imaging (MRI). In the intention-to-treat analysis, dapagliflozin significantly reduced LVM compared with placebo, with an absolute mean change of –2.82 g.

    Additional sensitivity analysis adjusting for baseline LVM, baseline blood pressure, weight, and SBP change showed the LVM change buy prozac fluoxetine online to remain statistically significant. Dapagliflozin significantly reduced pre-specified secondary endpoints including ambulatory 24-h SBP, nocturnal SBP, body weight, visceral adipose tissue, subcutaneous adipose tissue, insulin resistance, and high-sensitivity C-reactive protein. Figure 1Column bar charts showing the mean regression of left ventricular mass following dapagliflozin treatment compared to placebo (from Brown AJM, Gandy S, McCrimmon R, Houston JG, Struthers AD, Lang CC. A randomized controlled trial of dapagliflozin on left ventricular hypertrophy in buy prozac fluoxetine online people with type two diabetes.

    The DAPA-LVH trial. See pages 3421–3432).Figure 1Column bar charts showing the mean regression of left ventricular mass following dapagliflozin treatment compared to placebo (from Brown buy prozac fluoxetine online AJM, Gandy S, McCrimmon R, Houston JG, Struthers AD, Lang CC. A randomized controlled trial of dapagliflozin on left ventricular hypertrophy in people with type two diabetes. The DAPA-LVH trial.

    See pages 3421–3432).Lang and colleagues conclude buy prozac fluoxetine online that dapagliflozin treatment significantly reduced LVM in patients with T2D and LVH. The regression of LVM suggests that dapagliflozin can initiate reverse remodelling and changes in left ventricular structure that may partly contribute to cardioprotective effects of dapagliflozin. This manuscript is accompanied by an Editorial by Francesco Paneni from the University of Zurich in Switzerland and colleagues.8 They note that the above-mentioned effects of SGLT2 inhibitors set the ground for a possible beneficial effect of these drugs in patients with HFpEF, where microvascular dysfunction, cardiomyocyte inflammation, and cardiometabolic alterations take centre stage.While several landmark studies have long established that implantable cardioverter-defibrillator (ICD) therapy improves survival for primary prevention of sudden cardiac death ,9 risk stratification parameters and methods for this purpose are clinically underused. In a buy prozac fluoxetine online clinical research article entitled ‘Clinical effectiveness of primary prevention implantable cardioverter-defibrillators.

    Results of the EU-CERT-ICD controlled multicentre cohort study’ Markus Zabel from the Universitätsmedizin Göttingen in Germany and colleagues from the EU-CERT-ICD Study Investigators assessed the current clinical effectiveness of primary prevention by ICD therapy in a prospective investigator-initiated, controlled cohort study, conducted in 44 centres and 15 European countries. The study sought to assess current clinical effectiveness of primary prophylactic ICD implantation.10 The authors recruited buy prozac fluoxetine online 2327 patients with ischaemic or dilated cardiomyopathy and guideline indications for prophylactic ICD implantation. The primary endpoint was all-cause mortality. Baseline and follow-up data from 2247 patients were analysable.

    1516 patients with first ICD implantation (ICD group) and 731 patients without ICD serving buy prozac fluoxetine online as controls. Multivariable models and propensity scoring for adjustment were used to compare the two groups for mortality. Adjusted mortality associated with ICD vs. Control was significantly lower (hazard ratio 0.731) buy prozac fluoxetine online.

    Subgroup analyses indicated no ICD benefit in diabetics or in those aged ≥75 years. Figure 2Secondary efficacy endpoints comparing cardiosphere-derived cells and placebo at 6 months. Change in buy prozac fluoxetine online (A) left ventricular end-diastolic volume. (B) left ventricular end-systolic volume.

    And (C) buy prozac fluoxetine online N-terminal pro b-type natriuretic peptide levels. At 6 months. CDC, cardiosphere-derived cell. LVEDV, left ventricular end-diastolic buy prozac fluoxetine online volume.

    LVESV, left ventricular end-systolic volume. NT-proBNP, N-terminal pro b-type natriuretic peptide (from Makkar RR, Kereiakes DJ, Aguirre F, Kowalchuk G, Chakravarty T, Malliaras K, Francis GS, Povsic TJ, Schatz R, Traverse JH, Pogoda JM, Smith RR, Marbán L, Ascheim DD, Ostovaneh MR, Lima JAC, DeMaria A, Marbán E, Henry TD. Intracoronary ALLogeneic heart STem cells to Achieve myocardial buy prozac fluoxetine online Regeneration (ALLSTAR). A randomized, placebo-controlled, double-blinded trial.

    See pages 3451--3458).Figure 2Secondary efficacy endpoints comparing cardiosphere-derived cells and placebo at 6 months. Change in (A) buy prozac fluoxetine online left ventricular end-diastolic volume. (B) left ventricular end-systolic volume. And (C) N-terminal pro b-type natriuretic peptide buy prozac fluoxetine online levels.

    At 6 months. CDC, cardiosphere-derived cell. LVEDV, left ventricular end-diastolic volume buy prozac fluoxetine online. LVESV, left ventricular end-systolic volume.

    NT-proBNP, N-terminal pro b-type natriuretic peptide (from Makkar RR, Kereiakes DJ, Aguirre F, Kowalchuk G, Chakravarty T, Malliaras K, Francis GS, Povsic TJ, Schatz R, Traverse JH, Pogoda JM, Smith RR, Marbán L, Ascheim DD, Ostovaneh MR, Lima JAC, DeMaria A, Marbán E, Henry TD. Intracoronary ALLogeneic heart STem cells to buy prozac fluoxetine online Achieve myocardial Regeneration (ALLSTAR). A randomized, placebo-controlled, double-blinded trial. See pages 3451--3458).The authors conclude that in contemporary ischaemic/dilated cardiomyopathy patients (LVEF ≤35%, narrow QRS), primary prophylactic ICD treatment was buy prozac fluoxetine online associated with a substantial reduction in mortality, although this improvement was not consistent across the whole population.

    The manuscript is accompanied by an Editorial by N.A. Mark Estes III from the Heart and Vascular Institute UPMC in Pittsburgh, Pennsylvania, USA.11 The authors note that clinicians should be mindful of available risk stratification models and subgroup analyses from the EU-CERT-ICD and other studies. It follows that buy prozac fluoxetine online the process of shared decision-making should include careful consideration of the patient’s wishes and values, with an individualized assessment of potential benefit and risks of primary prevention of sudden death by ICD implantation.Cardiosphere-derived cells (CDCs) are cardiac progenitor cells which exhibit disease-modifying bioactivity in various models of cardiomyopathy and in previous clinical studies of acute myocardial infarction (MI), dilated cardiomyopathy, and Duchenne muscular dystrophy.12,13 In a clinical research article entitled ‘Intracoronary ALLogeneic heart STem cells to Achieve myocardial Regeneration (ALLSTAR). A randomized, placebo-controlled, double-blinded trial’, Raj Makkar from the Cedars-Sinai Heart Institute in Los Angeles, California, USA and colleagues assessed the safety and efficacy of intracoronary administration of allogeneic CDCs in the multicentre, randomized, double-blind, placebo-controlled, intracoronary ALLogeneic Heart STem Cells to Achieve Myocardial Regeneration (ALLSTAR) trial.14 The authors enrolled patients 4 weeks to 12 months after MI, with LVEF ≤45% and left ventricular LV scar size ≥15% of LVM by MRI.

    A pre-specified interim analysis was performed when 6-month MRI data were available. The trial was subsequently stopped due to the low probability of detecting a buy prozac fluoxetine online significant treatment effect of CDCs based on the primary endpoint. Patients were randomly allocated in a 2:1 ratio to receive CDCs or placebo in the infarct-related artery by the stop–flow technique. The primary safety endpoint was the occurrence, during 1-month post-intracoronary infusion, of acute myocarditis attributable to allogeneic CDCs, ventricular tachycardia- or ventricular fibrillation-related death, sudden unexpected death, or a major adverse cardiac event (death or hospitalization for HF or non-fatal MI).

    The primary efficacy endpoint was the relative percentage change buy prozac fluoxetine online in infarct size at 12 months post-infusion as assessed by contrast-enhanced cardiac MRI. Makkar and colleagues randomly allocated 90 patients to the CDC group and 44 to the placebo group. The mean baseline LVEF was 40% and the mean scar size was 22% of the buy prozac fluoxetine online LVM. No primary safety endpoint events occurred.

    There was no difference in the percentage change from baseline in scar size between CDC and placebo groups at 6 months. Compared with placebo, there were significant reductions in LV end-diastolic volume, LV buy prozac fluoxetine online end-systolic volume, and NT-proBNP at 6 months in CDC-treated patients.The authors conclude that intracoronary infusion of allogeneic CDCs in patients with post-MI left ventricular dysfunction was safe but did not reduce scar size relative to placebo at 6 months. The manuscript is accompanied by an Editorial by Francisco Fernandez-Aviles from the Hospital General Universitario Gregorio Marañón in Madrid, Spain and colleagues.15 The authors feel that various points need to be better addressed before proceeding again to clinical trials, if we want to move the field of cardiovascular regenerative and reparative medicine forward, for the sake of the cardiovascular health of millions of patients.Treatment of pathological cardiac remodelling and subsequent HF represents an unmet clinical need. Long non-coding RNAs (lncRNAs) are emerging as crucial molecular orchestrators of disease processes including that of heart diseases.16,17 In a Basic Science article entitled ‘Targeting muscle-enriched long non-coding RNA H19 reverses pathological cardiac hypertrophy’, Thomas Thum from the Hannover Medical School in Germany, and colleagues report on the powerful therapeutic potential of the conserved lncRNA H19 in the treatment of pathological cardiac hypertrophy.18 Pressure overload-induced left ventricular cardiac remodelling revealed an up-regulation of H19 in the early phase, but a strong sustained repression upon reaching the decompensated phase of HF.

    The translational potential of H19 was highlighted by its repression in a large animal (pig) model of LVH, in diseased human heart samples, in human stem cell-derived cardiomyocytes, and in human engineered heart tissue in buy prozac fluoxetine online response to afterload enhancement. Pressure overload-induced cardiac hypertrophy in H19 knockout mice was aggravated compared with wild-type mice. In contrast, vector-based, cardiomyocyte-directed gene therapy using murine but also human H19 buy prozac fluoxetine online strongly attenuated HF even when cardiac hypertrophy was already established. Mechanistically, using microarray, gene set enrichment analyses, and chromatin immunoprecipitation-DNA sequencing, the authors identified a link between H19 and prohypertrophic nuclear factor of activated T cells (NFAT) signalling.

    H19 physically interacts with the polycomb repressive complex 2 to suppress H3K27 tri-methylation of the antihypertrophic Tescalcin locus which in turn leads to reduced NFAT expression and activity.Thum and colleagues conclude that H19 is highly conserved and down-regulated in failing hearts from mice, pigs, and humans. H19 gene therapy prevents and reverses experimental pressure buy prozac fluoxetine online overload-induced HF. H19 acts as an antihypertrophic lncRNA and represents a promising therapeutic target to combat pathological cardiac remodelling. The manuscript is accompanied by an Editorial by Gianluigi Condorelli from the Humanitas University in Rozzano, Italy and colleagues.

    The authors note buy prozac fluoxetine online that dysregulation of epigenetic mechanisms leading to aberrant loss of cardiomyocyte homeostasis is a critical point to consider in understanding the onset of cardiovascular pathologies. Thus exploiting lncRNAs as therapeutic agents in myocardial disease could pave the way for efficaciously combatting one of the greatest healthcare burdens worldwide.19With the advent of omics, an innovative inductive method has provided researchers with possible ways new to monitor health and disease. This approach incorporates data from studies of the genome, transcriptome, proteome, and metabolome to focus on the assessment of a varied range of biomolecules.20 In a clinical review article entitled ‘Omics phenotyping in heart failure. The next frontier’ Antoni Bayes-Genis from the Cardiology Service, Hospital Universitari Germans Trias i Pujol in Badalona, Spain and colleagues provide a state-of-the-art review aiming to provide an up-to-date look at breakthrough omic technologies that are helping to unravel HF disease mechanisms buy prozac fluoxetine online and heterogeneity.21 Genomics, transcriptomics, proteomics, and metabolomics in HF are reviewed in depth.

    In addition, there is a thorough, expert discussion regarding the value of omics in identifying novel disease pathways, advancing understanding of disease mechanisms, differentiating HF phenotypes, yielding biomarkers for diagnosis or prognosis, or identifying new therapeutic targets in HF. The combination of multiple omics technologies may create a more comprehensive picture of the factors and pathophysiology involved in HF than achieved by either one alone, buy prozac fluoxetine online and provides a rich resource for predictive phenotype modelling. However, the successful translation of omics tools as solutions to clinical HF requires that the observations are robust and reproducible, and can be validated across multiple independent populations to ensure confidence in clinical decision-making.This issue is also complemented by a Discussion Forum contribution. In a contribution entitled ‘Heart failure development in obesity.

    Mechanistic pathways’ Kristjan Karason from the Sahlgrenska University buy prozac fluoxetine online Hospital in Gothenburg, Sweden and colleagues provide a reply to a recent comment entitled ‘Incident heart failure risk after bariatric surgery. The role of epicardial fat’.22,23The editors hope that this issue of the European Heart Journal will be of interest to its readers.With thanks to Amelia Meier-Batschelet, Johanna Hugger, and Martin Meyer for help with compilation of this article. References1Docherty KF, Jhund PS, Inzucchi SE, Køber L, Kosiborod MN, Martinez FA, Ponikowski P, DeMets DL, Sabatine MS, Bengtsson O, Sjöstrand M, Langkilde AM, Desai AS, Diez M, Howlett JG, Katova T, Ljungman CEA, O’Meara E, Petrie MC, Schou M, Verma S, Vinh PN, Solomon SD, McMurray JJV. Effects of dapagliflozin in DAPA-HF according to background heart buy prozac fluoxetine online failure therapy.

    Eur Heart J 2020;41:2379–2392.2Ponikowski P, Voors AA,, Anker SD, Bueno H, Cleland JGF, Coats AJS, Falk V, González-Juanatey JR, Harjola VP, Jankowska EA, Jessup M, Linde C, Nihoyannopoulos P, Parissis JT, Pieske B, Riley JP, Rosano GMC, Ruilope LM, Ruschitzka F, Rutten FH, van der Meer P. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. The Task Force for the buy prozac fluoxetine online diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC.

    Eur Heart J 2016;37:2129–2200.3Packer M buy prozac fluoxetine online. Are the benefits of SGLT2 inhibitors in heart failure and a reduced ejection fraction influenced by background therapy?. Expectations and realities of a new standard of care. Eur Heart J 2020;41:2393–2396.4Butler J, Zannad F, Filippatos buy prozac fluoxetine online G, Anker SD, Packer M.

    Totality of evidence in trials of sodium–glucose co-transporter-2 inhibitors in the patients with heart failure with reduced ejection fraction. Implications for clinical practice. Eur Heart J 2020;41:3398–3401.5Serenelli M, Böhm M, Inzucchi SE, Køber L, Kosiborod MN, Martinez FA, Ponikowski P,, Sabatine MS, Solomon SD, DeMets DL, Bengtsson O, Sjöstrand M, Langkilde AM, Anand IS, Chiang CE, Chopra VK, de Boer RA, Diez M, Dukát A, Ge J, Howlett JG, Katova T, Kitakaze M, Ljungman CEA, Verma buy prozac fluoxetine online S,, Docherty KF, Jhund PS, McMurray JJV. Effect of dapagliflozin according to baseline systolic blood pressure in the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure trial (DAPA-HF).

    Eur Heart J buy prozac fluoxetine online 2020;41:3402–3418.6Savarese G, Cosentino F. The interaction between dapagliflozin and blood pressure in heart failure. New evidence dissipating concerns. Eur Heart J 2020;41:3419–3420.7Brown AJM, Gandy S, McCrimmon R, Houston JG, Struthers buy prozac fluoxetine online AD, Lang CC.

    A randomized controlled trial of dapagliflozin on left ventricular hypertrophy in people with type two diabetes. The DAPA-LVH trial. Eur Heart J 2020;41:3421–3432.8Paneni F, Costantino S, buy prozac fluoxetine online Hamdani N. Regression of left ventricular hypertrophy with SGLT2 inhibitors.

    Eur Heart J 2020;41:3433–3436.9Priori SG, Blomström-Lundqvist C, Mazzanti A, Blom N, Borggrefe M, Camm J, Elliott PM, Fitzsimons D, Hatala R, Hindricks G, Kirchhof P, Kjeldsen K, Kuck KH, Hernandez-Madrid A, Nikolaou N, Norekvål TM, Spaulding C, Van Veldhuisen DJ. 2015 ESC Guidelines for the management of patients buy prozac fluoxetine online with ventricular arrhythmias and the prevention of sudden cardiac death. The Task Force for the Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death of the European Society of Cardiology (ESC). Endorsed by buy prozac fluoxetine online.

    Association for European Paediatric and Congenital Cardiology (AEPC). Eur Heart J 2015;36:2793–2867.10Zabel M, Willems R, Lubinski A, Bauer A, Brugada J, Conen D, Flevari P, Hasenfuß G, Svetlosak M, Huikuri HV, Malik M, Pavlović N, Schmidt G, Sritharan R, Schlögl S, Szavits-Nossan J, Traykov V, Tuinenburg AE, Willich SN, Harden M, Friede T, Svendsen JH, Sticherling C, Merkely B. Clinical effectiveness of primary prevention buy prozac fluoxetine online implantable cardioverter-defibrillators. Results of the EU-CERT-ICD controlled multicentre cohort study.

    Eur Heart J 2020;41:3437–3447.11Estes MNA, Saba S. Primary prevention of sudden buy prozac fluoxetine online death with the implantable cardioverter defibrillator. Bridging the evidence gap. Eur Heart J 2020;41:3448–3450.12Aminzadeh MA, Tseliou E, Sun B, Cheng K, Malliaras K, Makkar RR, Marbán E.

    Therapeutic efficacy of cardiosphere-derived cells in a transgenic mouse buy prozac fluoxetine online model of non-ischaemic dilated cardiomyopathy. Eur Heart J 2015;36:751–762.13Fadini GP, Mehta A, Dhindsa DS, Bonora BM, Sreejit G, Nagareddy P, Quyyumi AA. Circulating stem cells and cardiovascular outcomes buy prozac fluoxetine online. From basic science to the clinic.

    Eur Heart J 2020. Doi:10.1093/eurheartj/ehz923.14Makkar RR, Kereiakes DJ, Aguirre F, Kowalchuk G, Chakravarty T, Malliaras K, Francis GS, Povsic TJ, Schatz R, Traverse JH, Pogoda JM, buy prozac fluoxetine online Smith RR, Marbán L, Ascheim DD, Ostovaneh MR, Lima JAC, DeMaria A, Marbán E, Henry TD. Intracoronary ALLogeneic heart STem cells to Achieve myocardial Regeneration (ALLSTAR). A randomized, placebo-controlled, double-blinded trial.

    Eur Heart buy prozac fluoxetine online J 2020;41:3451–3458.15Sanz-Ruiz R, Fernández-Avilés F. Cardiovascular regenerative and reparative medicine. Is myocardial infarction buy prozac fluoxetine online the model?. Eur Heart J 2020;41:3459–3461.16Ounzain S, Micheletti R, Beckmann T, Schroen B, Alexanian M, Pezzuto I, Crippa S, Nemir M, Sarre A, Johnson R, Dauvillier J, Burdet F, Ibberson M, Guigó R, Xenarios I, Heymans S, Pedrazzini T.

    Genome-wide profiling of the cardiac transcriptome after myocardial infarction identifies novel heart-specific long non-coding RNAs. Eur Heart J 2015;36:353–368.17Lüscher buy prozac fluoxetine online TF. Novel molecular mechanisms of vascular disease. Non-coding RNAs, inflammation, and radiation.

    Eur Heart buy prozac fluoxetine online J. 2020;40:2467–2470.18Viereck J, Bührke A, Foinquinos A, Chatterjee S, Kleeberger JA, Xiao K, Janssen-Peters H, Batkai S, Ramanujam D, Kraft T, Cebotari S, Gueler F, Beyer AM, Schmitz J, Bräsen JH, Schmitto JD, Gyöngyösi M, Löser A, Hirt MN, Eschenhagen T, Engelhardt S, Bär C, Thum T. Targeting muscle-enriched long non-coding RNA H19 reverses pathological cardiac hypertrophy. Eur Heart J 2020;41:3462–3474.19Pagiatakis buy prozac fluoxetine online C, Hall IF, Condorelli G.

    Long non-coding RNA H19. A new avenue for buy prozac fluoxetine online RNA therapeutics in cardiac hypertrophy?. Eur Heart J 2020;41:3475–3476.20Hoogeveen RM, Pereira JPB, Nurmohamed NS, Zampoleri V, Bom MJ, Baragetti A, Boekholdt SM, Knaapen P, Khaw KT, Wareham NJ, Groen AK, Catapano AL, Koenig W, Levin E, Stroes ESG. Improved cardiovascular risk prediction using targeted plasma proteomics in primary prevention.

    Eur Heart buy prozac fluoxetine online J 2020;ehaa648. 21Bayes-Genis A, Liu PP, Lanfear DE, de Boer RA, González A, Thum T, Emdin M, Januzzi JL. Omics phenotyping in heart failure. The next frontier buy prozac fluoxetine online.

    Eur Heart J 2020;41:3477–3484.22Karason K, Jamaly S. Heart failure buy prozac fluoxetine online development in obesity. Mechanistic pathways. Eur Heart J 2020;41:3485.23van Woerden G, van Veldhuisen SL, Rienstra M.

    Incident heart failure risk after bariatric buy prozac fluoxetine online surgery. The role of epicardial fat. Eur Heart J 2020;41:1775. Published on behalf of the European Society of Cardiology buy prozac fluoxetine online.

    All rights reserved. © The Author(s) 2020. For permissions, please buy prozac fluoxetine online email. Journals.permissions@oup.com. For the podcast associated with this article, please visit https://academic.oup.com/eurheartj/pages/Podcasts.This Focus Issue on heart failure (HF) provides novel clinically relevant information on sodium–glucose co-transporter-2 (SGLT2) inhibitors which, initially proposed for the treatment of type 2 diabetes mellitus (T2D), have been found to improve the outcome of HF with reduced ejection fraction (HFrEF) when administered on the top of drugs known to improve the outcome of HF and are recommended in current European Guidelines.1,2Acording to modelling estimates, when compared with http://www.amisdepasteur.fr/what-i-should-buy-with-prozac/ no neurohormonal blockade, the use of a broad-based combination of disease-modifying drugs at target doses in patients with HF may reduce the risk of death by as much as 75%.

    It is surprising that in spite of this powerful therapeutic armamentarium, <1% of patients with chronic HF are currently receiving recommended drugs at doses that have been shown to prolong life.3 The buy prozac fluoxetine online issue opens with a Current Opinion article entitled ‘Totality of evidence in trials of sodium–glucose co-transporter-2 inhibitors in the patients with heart failure with reduced ejection fraction. Implications for clinical practice’ by Milton Packer from the Baylor University Medical Center at Dallas in Texas, USA and colleagues. The authors provide a perspective on the totality of evidence with SGLT2 inhibitors in patients with HFrEF.4 This paper is the first to issue a call for a major change in clinical practice based on the concordant results of DAPA-HF and EMPEROR-Reduced trials. The analyses and interpretations that are presented in this manuscript will undoubtedly generate considerable discussion and debate for a long time.Concern about buy prozac fluoxetine online hypotension often leads to withholding of beneficial therapy in patients with HFrEF.

    In a clinical research manuscript entitled ‘Effect of dapagliflozin according to baseline systolic blood pressure in the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure trial (DAPA-HF)’ John McMurray from the Western Infirmary in Glasgow, UK and colleagues on behalf of the DAPA-HF Investigators and Committees evaluated the efficacy and safety of dapagliflozin according to baseline systolic blood pressure (SBP) in DAPA-HF trial.5 Key inclusion criteria were. New York Heart Association (NYHA) class II–IV, left ventricular ejection fraction (LVEF) ≤40%, elevated N-terminal probrain natriuretic peptide (NT-proBNP) level, and SBP ≥95 mmHg. The primary buy prozac fluoxetine online outcome was a composite of worsening HF or cardiovascular death. The efficacy and safety of dapagliflozin was examined using SBP as both a categorical and a continuous variable.

    The placebo-corrected reduction in SBP from baseline to 2 weeks with dapagliflozin was –2.54 mmHg. The benefit and safety of dapagliflozin buy prozac fluoxetine online were consistent across the range of SBP. Study drug discontinuation did not differ between dapagliflozin and placebo across the SBP categories examined.The authors conclude that dapagliflozin had a small effect on SBP in patients with HFrEF and was superior to placebo in improving outcomes, and well tolerated, across the range of SBP included in DAPA-HF. The manuscript is accompanied buy prozac fluoxetine online by an Editorial by Francesco Cosentino from the University Hospital Solna in Stockholm, Sweden who comments that altogether, the results of the current post-hoc analysis demonstrating efficacy and safety of dapagliflozin regardless of SBP values might significantly contribute to foster the implementation of dapagliflozin use in HF clinical practice by dissipating any potential safety concern linked with its hypotensive effects.6In a clinical research article entitled ‘A randomized controlled trial of dapagliflozin on left ventricular hypertrophy in people with type two diabetes.

    The DAPA-LVH trial’, Chim Lang from the University of Dundee in the UK and colleagues tested the hypothesis that dapagliflozin may regress left ventricular hypertrophy (LVH) in people with T2D.7 The authors randomly assigned 66 patients with T2D, LVH, and controlled blood pressure to receive dapagliflozin 10 mg once daily or placebo for 12 months. The primary endpoint was change in absolute left ventricular mass (LVM), assessed by cardiac magnetic resonance imaging (MRI). In the intention-to-treat analysis, dapagliflozin significantly reduced LVM compared with placebo, with an absolute mean change of buy prozac fluoxetine online –2.82 g. Additional sensitivity analysis adjusting for baseline LVM, baseline blood pressure, weight, and SBP change showed the LVM change to remain statistically significant.

    Dapagliflozin significantly reduced pre-specified secondary endpoints including ambulatory 24-h SBP, nocturnal SBP, body weight, visceral adipose tissue, subcutaneous adipose tissue, insulin resistance, and high-sensitivity C-reactive protein. Figure 1Column bar charts showing buy prozac fluoxetine online the mean regression of left ventricular mass following dapagliflozin treatment compared to placebo (from Brown AJM, Gandy S, McCrimmon R, Houston JG, Struthers AD, Lang CC. A randomized controlled trial of dapagliflozin on left ventricular hypertrophy in people with type two diabetes. The DAPA-LVH buy prozac fluoxetine online trial.

    See pages 3421–3432).Figure 1Column bar charts showing the mean regression of left ventricular mass following dapagliflozin treatment compared to placebo (from Brown AJM, Gandy S, McCrimmon R, Houston JG, Struthers AD, Lang CC. A randomized controlled trial of dapagliflozin on left ventricular hypertrophy in people with type two diabetes. The DAPA-LVH buy prozac fluoxetine online trial. See pages 3421–3432).Lang and colleagues conclude that dapagliflozin treatment significantly reduced LVM in patients with T2D and LVH.

    The regression of LVM suggests that dapagliflozin can initiate reverse remodelling and changes in left ventricular structure that may partly contribute to cardioprotective effects of dapagliflozin. This manuscript is accompanied by an Editorial by Francesco Paneni from the University of Zurich in Switzerland and colleagues.8 They note that the above-mentioned effects of SGLT2 inhibitors set the ground for a possible beneficial effect of these drugs in patients with HFpEF, where microvascular dysfunction, cardiomyocyte inflammation, and cardiometabolic alterations take centre stage.While several landmark studies have long established that implantable cardioverter-defibrillator (ICD) therapy improves survival for buy prozac fluoxetine online primary prevention of sudden cardiac death ,9 risk stratification parameters and methods for this purpose are clinically underused. In a clinical research article entitled ‘Clinical effectiveness of primary prevention implantable cardioverter-defibrillators. Results of the EU-CERT-ICD controlled multicentre cohort study’ Markus Zabel from the Universitätsmedizin Göttingen in Germany and colleagues from the EU-CERT-ICD Study Investigators assessed the current clinical effectiveness of primary prevention by ICD therapy in a prospective investigator-initiated, controlled cohort study, conducted in 44 centres and 15 European countries.

    The study sought to assess current clinical effectiveness of primary prophylactic ICD implantation.10 The authors recruited 2327 patients with ischaemic or dilated cardiomyopathy and guideline indications for prophylactic ICD buy prozac fluoxetine online implantation. The primary endpoint was all-cause mortality. Baseline and follow-up data from 2247 patients were buy prozac fluoxetine online analysable. 1516 patients with first ICD implantation (ICD group) and 731 patients without ICD serving as controls.

    Multivariable models and propensity scoring for adjustment were used to compare the two groups for mortality. Adjusted mortality buy prozac fluoxetine online associated with ICD vs. Control was significantly lower (hazard ratio 0.731). Subgroup analyses indicated no ICD benefit in diabetics or in those aged ≥75 years.

    Figure 2Secondary efficacy endpoints comparing cardiosphere-derived cells and placebo buy prozac fluoxetine online at 6 months. Change in (A) left ventricular end-diastolic volume. (B) left buy prozac fluoxetine online ventricular end-systolic volume. And (C) N-terminal pro b-type natriuretic peptide levels.

    At 6 months. CDC, cardiosphere-derived cell buy prozac fluoxetine online. LVEDV, left ventricular end-diastolic volume. LVESV, left ventricular end-systolic volume.

    NT-proBNP, N-terminal pro b-type natriuretic peptide (from Makkar RR, Kereiakes DJ, Aguirre F, Kowalchuk G, Chakravarty T, Malliaras K, Francis GS, Povsic TJ, Schatz R, Traverse JH, Pogoda JM, Smith RR, Marbán L, Ascheim DD, Ostovaneh MR, Lima JAC, DeMaria buy prozac fluoxetine online A, Marbán E, Henry TD. Intracoronary ALLogeneic heart STem cells to Achieve myocardial Regeneration (ALLSTAR). A randomized, placebo-controlled, double-blinded trial. See pages 3451--3458).Figure 2Secondary efficacy endpoints comparing cardiosphere-derived cells and placebo buy prozac fluoxetine online at 6 months.

    Change in (A) left ventricular end-diastolic volume. (B) left ventricular buy prozac fluoxetine online end-systolic volume. And (C) N-terminal pro b-type natriuretic peptide levels. At 6 months.

    CDC, cardiosphere-derived cell buy prozac fluoxetine online. LVEDV, left ventricular end-diastolic volume. LVESV, left ventricular end-systolic volume. NT-proBNP, N-terminal pro b-type natriuretic peptide (from Makkar RR, Kereiakes DJ, Aguirre F, Kowalchuk G, Chakravarty buy prozac fluoxetine online T, Malliaras K, Francis GS, Povsic TJ, Schatz R, Traverse JH, Pogoda JM, Smith RR, Marbán L, Ascheim DD, Ostovaneh MR, Lima JAC, DeMaria A, Marbán E, Henry TD.

    Intracoronary ALLogeneic heart STem cells to Achieve myocardial Regeneration (ALLSTAR). A randomized, placebo-controlled, double-blinded trial. See pages 3451--3458).The authors conclude that in contemporary ischaemic/dilated cardiomyopathy patients (LVEF buy prozac fluoxetine online ≤35%, narrow QRS), primary prophylactic ICD treatment was associated with a substantial reduction in mortality, although this improvement was not consistent across the whole population. The manuscript is accompanied by an Editorial by N.A.

    Mark Estes III from the Heart and Vascular Institute UPMC buy prozac fluoxetine online in Pittsburgh, Pennsylvania, USA.11 The authors note that clinicians should be mindful of available risk stratification models and subgroup analyses from the EU-CERT-ICD and other studies. It follows that the process of shared decision-making should include careful consideration of the patient’s wishes and values, with an individualized assessment of potential benefit and risks of primary prevention of sudden death by ICD implantation.Cardiosphere-derived cells (CDCs) are cardiac progenitor cells which exhibit disease-modifying bioactivity in various models of cardiomyopathy and in previous clinical studies of acute myocardial infarction (MI), dilated cardiomyopathy, and Duchenne muscular dystrophy.12,13 In a clinical research article entitled ‘Intracoronary ALLogeneic heart STem cells to Achieve myocardial Regeneration (ALLSTAR). A randomized, placebo-controlled, double-blinded trial’, Raj Makkar from the Cedars-Sinai Heart Institute in Los Angeles, California, USA and colleagues assessed the safety and efficacy of intracoronary administration of allogeneic CDCs in the multicentre, randomized, double-blind, placebo-controlled, intracoronary ALLogeneic Heart STem Cells to Achieve Myocardial Regeneration (ALLSTAR) trial.14 The authors enrolled patients 4 weeks to 12 months after MI, with LVEF ≤45% and left ventricular LV scar size ≥15% of LVM by MRI. A pre-specified interim analysis was performed when 6-month MRI data buy prozac fluoxetine online were available.

    The trial was subsequently stopped due to the low probability of detecting a significant treatment effect of CDCs based on the primary endpoint. Patients were randomly allocated in a 2:1 ratio to receive CDCs or placebo in the infarct-related artery by the stop–flow technique. The primary safety endpoint was the occurrence, during 1-month post-intracoronary infusion, of acute myocarditis attributable to allogeneic CDCs, ventricular tachycardia- or ventricular fibrillation-related death, sudden unexpected death, or buy prozac fluoxetine online a major adverse cardiac event (death or hospitalization for HF or non-fatal MI). The primary efficacy endpoint was the relative percentage change in infarct size at 12 months post-infusion as assessed by contrast-enhanced cardiac MRI.

    Makkar and colleagues randomly allocated 90 patients to the CDC group and buy prozac fluoxetine online 44 to the placebo group. The mean baseline LVEF was 40% and the mean scar size was 22% of the LVM. No primary safety endpoint events occurred. There was no difference in the percentage change from baseline in buy prozac fluoxetine online scar size between CDC and placebo groups at 6 months.

    Compared with placebo, there were significant reductions in LV end-diastolic volume, LV end-systolic volume, and NT-proBNP at 6 months in CDC-treated patients.The authors conclude that intracoronary infusion of allogeneic CDCs in patients with post-MI left ventricular dysfunction was safe but did not reduce scar size relative to placebo at 6 months. The manuscript is accompanied by an Editorial by Francisco Fernandez-Aviles from the Hospital General Universitario Gregorio Marañón in Madrid, Spain and colleagues.15 The authors feel that various points need to be better addressed before proceeding again to clinical trials, if we want to move the field of cardiovascular regenerative and reparative medicine forward, for the sake of the cardiovascular health of millions of patients.Treatment of pathological cardiac remodelling and subsequent HF represents an unmet clinical need. Long non-coding RNAs (lncRNAs) are emerging as crucial molecular orchestrators of disease processes including that of heart diseases.16,17 In a Basic Science article entitled ‘Targeting muscle-enriched long non-coding RNA H19 reverses pathological cardiac hypertrophy’, Thomas Thum from the Hannover Medical School in Germany, and colleagues report on the powerful therapeutic potential of the conserved lncRNA H19 in the treatment of pathological cardiac hypertrophy.18 Pressure overload-induced left ventricular cardiac remodelling revealed an up-regulation of H19 in the early phase, but a strong sustained repression buy prozac fluoxetine online upon reaching the decompensated phase of HF. The translational potential of H19 was highlighted by its repression in a large animal (pig) model of LVH, in diseased human heart samples, in human stem cell-derived cardiomyocytes, and in human engineered heart tissue in response to afterload enhancement.

    Pressure overload-induced cardiac hypertrophy in H19 knockout mice was aggravated compared with wild-type mice. In contrast, vector-based, cardiomyocyte-directed gene therapy using murine but also buy prozac fluoxetine online human H19 strongly attenuated HF even when cardiac hypertrophy was already established. Mechanistically, using microarray, gene set enrichment analyses, and chromatin immunoprecipitation-DNA sequencing, the authors identified a link between H19 and prohypertrophic nuclear factor of activated T cells (NFAT) signalling. H19 physically interacts with the polycomb repressive complex 2 to suppress H3K27 tri-methylation of the antihypertrophic Tescalcin locus which buy prozac fluoxetine online in turn leads to reduced NFAT expression and activity.Thum and colleagues conclude that H19 is highly conserved and down-regulated in failing hearts from mice, pigs, and humans.

    H19 gene therapy prevents and reverses experimental pressure overload-induced HF. H19 acts as an antihypertrophic lncRNA and represents a promising therapeutic target to combat pathological cardiac remodelling. The manuscript is accompanied by an Editorial by Gianluigi Condorelli from the buy prozac fluoxetine online Humanitas University in Rozzano, Italy and colleagues. The authors note that dysregulation of epigenetic mechanisms leading to aberrant loss of cardiomyocyte homeostasis is a critical point to consider in understanding the onset of cardiovascular pathologies.

    Thus exploiting lncRNAs as therapeutic agents in myocardial disease could pave the way for efficaciously combatting one of the greatest healthcare burdens worldwide.19With the advent of omics, an innovative inductive method has provided researchers with possible ways new to monitor health and disease. This approach incorporates data from studies of the genome, transcriptome, proteome, and metabolome to focus on the assessment of a varied range of biomolecules.20 In a clinical review article entitled ‘Omics phenotyping in heart buy prozac fluoxetine online failure. The next frontier’ Antoni Bayes-Genis from the Cardiology Service, Hospital Universitari Germans Trias i Pujol in Badalona, Spain and colleagues provide a state-of-the-art review aiming to provide an up-to-date look at breakthrough omic technologies that are helping to unravel HF disease mechanisms and heterogeneity.21 Genomics, transcriptomics, proteomics, and metabolomics in HF are reviewed in depth. In addition, there is a thorough, expert discussion regarding the value of omics in identifying novel disease pathways, advancing understanding of disease mechanisms, differentiating HF phenotypes, yielding biomarkers for diagnosis or prognosis, or identifying new therapeutic targets in HF.

    The combination buy prozac fluoxetine online of multiple omics technologies may create a more comprehensive picture of the factors and pathophysiology involved in HF than achieved by either one alone, and provides a rich resource for predictive phenotype modelling. However, the successful translation of omics tools as solutions to clinical HF requires that the observations are robust and reproducible, and can be validated across multiple independent populations to ensure confidence in clinical decision-making.This issue is also complemented by a Discussion Forum contribution. In a contribution entitled ‘Heart failure buy prozac fluoxetine online development in obesity. Mechanistic pathways’ Kristjan Karason from the Sahlgrenska University Hospital in Gothenburg, Sweden and colleagues provide a reply to a recent comment entitled ‘Incident heart failure risk after bariatric surgery.

    The role of epicardial fat’.22,23The editors hope that this issue of the European Heart Journal will be of interest to its readers.With thanks to Amelia Meier-Batschelet, Johanna Hugger, and Martin Meyer for help with compilation of this article. References1Docherty KF, Jhund PS, Inzucchi SE, Køber L, Kosiborod MN, Martinez FA, Ponikowski P, DeMets DL, Sabatine MS, buy prozac fluoxetine online Bengtsson O, Sjöstrand M, Langkilde AM, Desai AS, Diez M, Howlett JG, Katova T, Ljungman CEA, O’Meara E, Petrie MC, Schou M, Verma S, Vinh PN, Solomon SD, McMurray JJV. Effects of dapagliflozin in DAPA-HF according to background heart failure therapy. Eur Heart J 2020;41:2379–2392.2Ponikowski P, Voors AA,, Anker SD, Bueno H, Cleland JGF, Coats AJS, Falk V, González-Juanatey JR, Harjola VP, Jankowska EA, Jessup M, Linde C, Nihoyannopoulos P, Parissis JT, Pieske B, Riley JP, Rosano GMC, Ruilope LM, Ruschitzka F, Rutten FH, van der Meer P.

    2016 ESC buy prozac fluoxetine online Guidelines for the diagnosis and treatment of acute and chronic heart failure. The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the buy prozac fluoxetine online Heart Failure Association (HFA) of the ESC. Eur Heart J 2016;37:2129–2200.3Packer M.

    Are the benefits of SGLT2 inhibitors in heart failure and a reduced ejection fraction influenced by background therapy?. Expectations and realities of a buy prozac fluoxetine online new standard of care. Eur Heart J 2020;41:2393–2396.4Butler J, Zannad F, Filippatos G, Anker SD, Packer M. Totality of evidence in trials of sodium–glucose co-transporter-2 inhibitors in the patients with heart failure with reduced ejection fraction.

    Implications for clinical buy prozac fluoxetine online practice. Eur Heart J 2020;41:3398–3401.5Serenelli M, Böhm M, Inzucchi SE, Køber L, Kosiborod MN, Martinez FA, Ponikowski P,, Sabatine MS, Solomon SD, DeMets DL, Bengtsson O, Sjöstrand M, Langkilde AM, Anand IS, Chiang CE, Chopra VK, de Boer RA, Diez M, Dukát A, Ge J, Howlett JG, Katova T, Kitakaze M, Ljungman CEA, Verma S,, Docherty KF, Jhund PS, McMurray JJV. Effect of dapagliflozin according to baseline systolic blood pressure in the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure trial (DAPA-HF). Eur Heart J 2020;41:3402–3418.6Savarese G, Cosentino F buy prozac fluoxetine online.

    The interaction between dapagliflozin and blood pressure in heart failure. New evidence buy prozac fluoxetine online dissipating concerns. Eur Heart J 2020;41:3419–3420.7Brown AJM, Gandy S, McCrimmon R, Houston JG, Struthers AD, Lang CC. A randomized controlled trial of dapagliflozin on left ventricular hypertrophy in people with type two diabetes.

    The DAPA-LVH buy prozac fluoxetine online trial. Eur Heart J 2020;41:3421–3432.8Paneni F, Costantino S, Hamdani N. Regression of left ventricular hypertrophy with SGLT2 inhibitors. Eur Heart J 2020;41:3433–3436.9Priori SG, Blomström-Lundqvist C, Mazzanti A, Blom N, Borggrefe M, Camm J, Elliott PM, Fitzsimons D, Hatala R, Hindricks G, Kirchhof P, Kjeldsen K, Kuck KH, Hernandez-Madrid A, buy prozac fluoxetine online Nikolaou N, Norekvål TM, Spaulding C, Van Veldhuisen DJ.

    2015 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death. The Task Force for the Management of Patients with buy prozac fluoxetine online Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death of the European Society of Cardiology (ESC). Endorsed by. Association for European Paediatric and Congenital Cardiology (AEPC).

    Eur Heart J 2015;36:2793–2867.10Zabel M, Willems R, Lubinski A, Bauer A, Brugada J, Conen D, buy prozac fluoxetine online Flevari P, Hasenfuß G, Svetlosak M, Huikuri HV, Malik M, Pavlović N, Schmidt G, Sritharan R, Schlögl S, Szavits-Nossan J, Traykov V, Tuinenburg AE, Willich SN, Harden M, Friede T, Svendsen JH, Sticherling C, Merkely B. Clinical effectiveness of primary prevention implantable cardioverter-defibrillators. Results of the EU-CERT-ICD controlled multicentre cohort study. Eur Heart buy prozac fluoxetine online J 2020;41:3437–3447.11Estes MNA, Saba S.

    Primary prevention of sudden death with the implantable cardioverter defibrillator. Bridging the evidence gap. Eur Heart J 2020;41:3448–3450.12Aminzadeh MA, buy prozac fluoxetine online Tseliou E, Sun B, Cheng K, Malliaras K, Makkar RR, Marbán E. Therapeutic efficacy of cardiosphere-derived cells in a transgenic mouse model of non-ischaemic dilated cardiomyopathy.

    Eur Heart J buy prozac fluoxetine online 2015;36:751–762.13Fadini GP, Mehta A, Dhindsa DS, Bonora BM, Sreejit G, Nagareddy P, Quyyumi AA. Circulating stem cells and cardiovascular outcomes. From basic science to the clinic. Eur Heart J 2020 buy prozac fluoxetine online.

    Doi:10.1093/eurheartj/ehz923.14Makkar RR, Kereiakes DJ, Aguirre F, Kowalchuk G, Chakravarty T, Malliaras K, Francis GS, Povsic TJ, Schatz R, Traverse JH, Pogoda JM, Smith RR, Marbán L, Ascheim DD, Ostovaneh MR, Lima JAC, DeMaria A, Marbán E, Henry TD. Intracoronary ALLogeneic heart STem cells to Achieve myocardial Regeneration (ALLSTAR). A randomized, placebo-controlled, double-blinded buy prozac fluoxetine online trial. Eur Heart J 2020;41:3451–3458.15Sanz-Ruiz R, Fernández-Avilés F.

    Cardiovascular regenerative and reparative medicine. Is myocardial buy prozac fluoxetine online infarction the model?. Eur Heart J 2020;41:3459–3461.16Ounzain S, Micheletti R, Beckmann T, Schroen B, Alexanian M, Pezzuto I, Crippa S, Nemir M, Sarre A, Johnson R, Dauvillier J, Burdet F, Ibberson M, Guigó R, Xenarios I, Heymans S, Pedrazzini T. Genome-wide profiling of the buy prozac fluoxetine online cardiac transcriptome after myocardial infarction identifies novel heart-specific long non-coding RNAs.

    Eur Heart J 2015;36:353–368.17Lüscher TF. Novel molecular mechanisms of vascular disease. Non-coding RNAs, buy prozac fluoxetine online inflammation, and radiation. Eur Heart J.

    2020;40:2467–2470.18Viereck J, Bührke A, Foinquinos A, Chatterjee S, Kleeberger JA, Xiao K, Janssen-Peters H, Batkai S, Ramanujam D, Kraft T, Cebotari S, Gueler F, Beyer AM, Schmitz J, Bräsen JH, Schmitto JD, Gyöngyösi M, Löser A, Hirt MN, Eschenhagen T, Engelhardt S, Bär C, Thum T. Targeting muscle-enriched long non-coding buy prozac fluoxetine online RNA H19 reverses pathological cardiac hypertrophy. Eur Heart J 2020;41:3462–3474.19Pagiatakis C, Hall IF, Condorelli G. Long non-coding buy prozac fluoxetine online RNA H19.

    A new avenue for RNA therapeutics in cardiac hypertrophy?. Eur Heart J 2020;41:3475–3476.20Hoogeveen RM, Pereira JPB, Nurmohamed NS, Zampoleri V, Bom MJ, Baragetti A, Boekholdt SM, Knaapen P, Khaw KT, Wareham NJ, Groen AK, Catapano AL, Koenig W, Levin E, Stroes ESG. Improved cardiovascular risk prediction using targeted plasma proteomics in buy prozac fluoxetine online primary prevention. Eur Heart J 2020;ehaa648.

    21Bayes-Genis A, Liu PP, Lanfear DE, de Boer RA, González A, Thum T, Emdin M, Januzzi JL. Omics phenotyping buy prozac fluoxetine online in heart failure. The next frontier. Eur Heart J 2020;41:3477–3484.22Karason K, Jamaly S.

    Heart failure development buy prozac fluoxetine online in obesity. Mechanistic pathways. Eur Heart J 2020;41:3485.23van Woerden G, van Veldhuisen buy prozac fluoxetine online SL, Rienstra M. Incident heart failure risk after bariatric surgery.

    The role of epicardial fat. Eur Heart buy prozac fluoxetine online J 2020;41:1775. Published on behalf of the European Society of Cardiology. All rights reserved.

    © The Author(s) 2020 buy prozac fluoxetine online. For permissions, please email. Journals.permissions@oup.com..

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