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What's kamagra online uk included?. Daily reporting and analysis The most comprehensive industry coverage from a powerhouse team of reporters Subscriber-only newsletters Daily newsletters to brief you on the most important industry news of the day STAT+ Conversations Weekly opportunities to engage with our reporters and leading industry experts in live video conversations Exclusive industry events Premium access to subscriber-only networking events around the country The best reporters in the industry The most trusted and well-connected newsroom in the health care industry And much more Exclusive interviews with industry leaders, profiles, and premium tools, like our CRISPR Trackr.Unlock this article by subscribing to STAT+ and enjoy your first 30 days free!. GET STARTED Log In | Learn More What is it?. STAT+ is STAT's premium subscription service for in-depth biotech, pharma, policy, and life science coverage and analysis kamagra online uk. Our award-winning team covers news on Wall Street, policy developments in Washington, early science breakthroughs and clinical trial results, and health care disruption in Silicon Valley and beyond.

What's included?. Daily reporting and analysis The most comprehensive industry coverage from a powerhouse team of reporters Subscriber-only newsletters Daily newsletters to brief you on the most important industry news of the day STAT+ Conversations Weekly opportunities to engage with our reporters and leading industry experts in live video conversations Exclusive industry events Premium access to subscriber-only networking events around the country The best reporters in the industry The most trusted and well-connected newsroom in the health care industry And much more Exclusive interviews with industry leaders, profiles, and premium tools, like our CRISPR Trackr..

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As part of our ongoing commitment to prioritizing healing and humanity as we stand against social injustice, Mathematica is pleased to announce is kamagra safe to use that President and CEO Paul Decker is joining more than 1,300 CEOs and business leaders as a member of CEO Action for Diversity and Web Site Inclusion™. This coalition represents the largest CEO-driven business commitment to advancing workplace diversity, equity, and inclusion, while working to ensure opportunity at the highest levels of corporate leadership.“During a time when the nation continues to be tested by unresolved issues of social justice, Mathematica has taken significant strides toward centering diversity, equity, and inclusion in our interactions with each other and in our approach to our work,” said Decker. €œToday, we’re taking another important step forward by joining CEO Action for Diversity and Inclusion, an organization that unites business is kamagra safe to use leaders from around the world to advance DEI initiatives in our own workplaces and beyond.

I’m honored to represent Mathematica in this coalition fighting for meaningful change.”CEO Action represents approximately 13 million employees across more than 85 industries. As a member through its CEO, Mathematica has committed to dedicating time and resources to advancing diversity, equity, and inclusion both within Mathematica and as part of the CEO Action network. Decker has also taken the CEO Action is kamagra safe to use pledge to “check my bias, speak up for others and show up for all.”A 100% employee-owned company, Mathematica works with private- and public-sector agencies, corporations, and foundations around the world, using data and evidence to improve the lives of people and communities.

About CEO Action for Diversity &. Inclusion™ CEO Action is kamagra safe to use for Diversity &. Inclusion™ is the largest CEO-driven business commitment to advance diversity and inclusion within the workplace.

Bringing together more than 1,000 CEOs of America’s leading organizations, the commitment outlines actions that participating companies pledge to take to cultivate a workplace where diverse perspectives and experiences are welcomed and respected, employees feel comfortable and encouraged to discuss diversity and inclusion, and where best known—and successful—actions can be shared across organizations. Learn more at CEOAction.com and connect is kamagra safe to use with them on Twitter. @CEOAction.

For more information, please contact:Jennifer de Vallancejdevallance@mathematica-mpr.com202-484-4692.

As part of our ongoing commitment to prioritizing healing kamagra online uk and humanity as we stand against social injustice, Mathematica is pleased to https://friederichsseed.com/zithromax-generic-cost//////////// announce that President and CEO Paul Decker is joining more than 1,300 CEOs and business leaders as a member of CEO Action for Diversity and Inclusion™. This coalition represents the largest CEO-driven business commitment to advancing workplace diversity, equity, and inclusion, while working to ensure opportunity at the highest levels of corporate leadership.“During a time when the nation continues to be tested by unresolved issues of social justice, Mathematica has taken significant strides toward centering diversity, equity, and inclusion in our interactions with each other and in our approach to our work,” said Decker. €œToday, we’re taking another important step forward by joining CEO Action for Diversity and Inclusion, an organization that unites business leaders from around the world to advance DEI initiatives in our own workplaces kamagra online uk and beyond. I’m honored to represent Mathematica in this coalition fighting for meaningful change.”CEO Action represents approximately 13 million employees across more than 85 industries. As a member through its CEO, Mathematica has committed to dedicating time and resources to advancing diversity, equity, and inclusion both within Mathematica and as part of the CEO Action network.

Decker has also taken the CEO Action pledge to “check my bias, speak up for others and show up for all.”A 100% employee-owned company, Mathematica works with private- and public-sector agencies, corporations, and kamagra online uk foundations around the world, using data and evidence to improve the lives of people and communities. About CEO Action for Diversity &. Inclusion™ CEO Action for Diversity & kamagra online uk. Inclusion™ is the largest CEO-driven business commitment to advance diversity and inclusion within the workplace. Bringing together more than 1,000 CEOs of America’s leading organizations, the commitment outlines actions that participating companies pledge to take to cultivate a workplace where diverse perspectives and experiences are welcomed and respected, employees feel comfortable and encouraged to discuss diversity and inclusion, and where best known—and successful—actions can be shared across organizations.

Learn more at CEOAction.com and kamagra online uk connect with them on Twitter. @CEOAction. For more information, please contact:Jennifer de Vallancejdevallance@mathematica-mpr.com202-484-4692.

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Getting diagnosed with depression kamagra sex brings up different emotions for different people Cialis 20mg price. After your doctor or mental health provider gives you the news, it’s a good idea to reach out for support from family, friends, or others in your community. They may be able to help you process what you’re kamagra sex feeling.“For some people there’s relief. Here’s an answer that explains what’s going on with you.

It’s a medical condition and it’s highly kamagra sex treatable,” says Ashley J. Smith, PhD, a licensed clinical psychologist in Kansas City, MO, and co-founder of the psychological center Peak Mind.Other people struggle with the diagnosis, she says. You might think. €œâ€˜I have kamagra sex depression.

What does that mean about me?. Am I flawed kamagra sex or broken?. €™â€Learning you have a mood disorder can be tough to hear. You could even feel ashamed if your family or community dismisses mental health conditions, says Jameca Cooper, kamagra sex PhD, a counseling psychologist in St.

Louis and president and clinical director of Emergence Psychological Services. €œA lot of my patients talk about how their families don’t really believe in mental health issues like depression or anxiety,” Cooper says. €œSometimes they refer to kamagra sex baby boomer parents that say, ‘Just suck it up. Get over it.

Just get kamagra sex enough rest. Just work harder.’ ... A lot of kamagra sex people’s families see mental health as a weakness.”Some people come from communities that don’t believe in mental health diagnoses, she adds. €œIn their countries of origin there is no such thing as anxiety or depression or schizophrenia.

They might call it something else, and they might lump all of them together.”Smith, who’s a member of the Anxiety &. Depression Association of America, recommends educating yourself kamagra sex and your loved ones about depression by checking out reputable sources, like the ADAA’s website. €œThere [are] myths out there, and you need to understand. €˜Here’s the kamagra sex actual science, here’s what we actually know about it.’ And that can help dispel some of those myths and criticisms,” Smith says.

€œâ€˜We have to work hard to help people understand that mental illness has nothing to do with your character,” she adds. €œIt has nothing to do kamagra sex with your value as a human, your intelligence. It’s neurobiological.”Who to Ask for SupportIf your family and close friends accept that mental health conditions are serious health conditions, talk to them about your depression diagnosis, Cooper and Smith say.“We need strong supports. We need healthy relationships.

And you need that kamagra sex more than ever when you’re experiencing depression,” Smith says. €œBeing open with the people in your life helps maintain those connections, which is a protective factor.”A candid conversation could also help them understand what you’ve been going through if depression has been making you irritable, negative, or uncommunicative, she says. That way, they can give you encouragement and help you stick to your treatment.Tell kamagra sex your loved ones what kind of support you need, Cooper says. Try to be specific.

Maybe you just need understanding and patience, rather than frequent phone calls kamagra sex to check in on you. Or maybe you’d appreciate an occasional hand with certain responsibilities, like help making meals or someone to pick the kids up from school. If you’ve heard your loved ones mock or disregard mental health issues in the past, you can still try to educate them about your diagnosis. But you might want to look elsewhere kamagra sex for guidance and understanding, Cooper says.You can connect with people outside of your family and friends, too.

A local or virtual support group for depression is one good option. There, you can meet people who understand what you’re going through, and they may be able to give you tips kamagra sex that helped them. A support group can be especially helpful if other things in your life are playing a role in your depression, like a serious health condition or ongoing grief from a personal loss, Cooper says.If you’re religious, you can also make your faith a part of your healing process. For example, kamagra sex some churches offer support groups and different types of counseling, Cooper says.Getting support specifically for depression is key, but you can benefit from indirect emotional boosts, too.

For example, you could volunteer for a cause that makes you feel good, Smith says. €œWhen you’re finding a sense of meaning and purpose, when you’re engaging with other people, when you’re doing activities that matter, those can help actually address some symptoms of depression,” she says. Physical activity is a great way to help take charge of kamagra sex depression, she adds. €œA gym or exercise can also provide that sense of community and of support while also getting that exercise in.”As you come to grips with your diagnosis and find emotional support, work closely with your doctor oror mental health provider.

Ask them which treatments and lifestyle changes might help you feel your best kamagra sex. €œThere’s a lot of different pathways that can lead to depression,” Smith says. €œSo that also means we have a lot of different treatment options that can work.”July 28, 2201 -- About half of adults in the United States say that they would be uncomfortable seeing kamagra sex a doctor who had not been vaccinated against erectile dysfunction treatment, according to a recent WebMD/Medscape poll. In the survey, 54% of the 687 respondents said that they would be “not at all comfortable” seeing an unvaccinated doctor, with 9% selecting the “somewhat comfortable” option, while more than a third (37%) said they would be “very comfortable” in that situation.

Women and men largely agreed on their level of comfort. 58% of women and 57% of men said not at all, 7% of women and 10% of men said somewhat, and 35% of women and 33% of men said vaccination status did not matter to them, based on kamagra sex the responses received during data collection on July 8-9, 2021. As with so many things American these days, however, there are some significant differences hiding in those findings. Age differences, for example, played a major role in the results, with 64% of those ages 45 years and older kamagra sex saying they were not at all comfortable, vs.

46% of those under age 45. Respondents living in the West were most kamagra sex likely to express their comfort with nonvaccinated doctors (46%), and those in the Northeast were least likely (26%), with the Midwest (35%) and the South (38%) falling in between. Scenarios. Should Providers Be Punished?.

The survey also included a question about whether health care providers should be kamagra sex punished if they expose others to erectile dysfunction treatment through various scenarios while at work. The scenario voted worst was a clinician who had erectile dysfunction treatment but continued to work without using personal protective equipment (PPE). Eighty-two percent kamagra sex of respondents agreed that was worthy of punishment. A clinician who knew they were infected but continued to work while wearing PPE was the only other scenario where more than half of the respondents supported punishment (53%).

Doctors, physician assistants, kamagra sex nurses, pharmacists, and other health care providers were also asked similar questions. That poll surveyed 2,498 professionals and was conducted July 7-18. That group came to a similar conclusion. More than 90% said that the clinician who knew they were infected but kept working without PPE kamagra sex should be punished.

The opinions in that survey differed somewhat after that, both from the patient poll and between the clinician groups. None of the other scenarios reached 50% support for punishment among the doctors, but 51% of nurses and 55% of other providers wanted kamagra sex to punish a clinician known to have erectile dysfunction treatment who infected a vulnerable patient. WebMD Health News Sources WebMD/Medscape polls, July 8-9, 2021, July 7-18, 2021. © 2021 WebMD, kamagra sex LLC.

All rights reserved.SOURCES. Annie Miller, behavioral sleep medicine therapist, DC Metro Sleep and Psychotherapy. Mayo Clinic kamagra sex. €œInsomnia treatment.

Cognitive behavioral therapy instead kamagra sex of sleeping pills.” Kaur, H. Spurling, B. Bollu, P kamagra sex. Chronic Insomnia, StatPearls Publishing, 2021.

Sleep Foundation. €œLight Therapy for Insomnia Sufferers,” “Sleep Hygiene,” “Light and Sleep,” “Mental Health and Sleep.” Stanford Health kamagra sex Care. €œStimulus Control and CBTI.”If you’re one of the millions of people who have trouble sleeping, you may have considered a cannabis compound, such as CBD. Some say cannabis compounds are kamagra sex helpful, but more research is needed.

And they might not be legal, depending on where you live. Look up the laws to know what’s allowed.What Does the Research Say About kamagra sex Cannabis?. Also known as marijuana, there’s growing interest in the health benefits of cannabis, specifically cannabis compounds. Two cannabinoids that get a lot of attention are:Tetrahydrocannabinol (THC).

The compound in cannabis that kamagra sex makes you feel high. Human-made versions are used to ease nausea and vomiting from cancer treatment.Cannabidiol (CBD). A compound in cannabis said to have kamagra sex anti-inflammatory and anti-seizure properties. It does not make you feel high.Research results on cannabis and sleep are mixed.

So far, there haven’t been many controlled studies to show that THC, CBD, or a combination of both can boost sleep quality, says kamagra sex Bhanuprakash (Bhanu) Kolla, MD. He’s an associate professor of psychiatry and psychology and a consultant for Mayo Clinic’s Center for Sleep Medicine in Rochester, MN. But some studies show promise. That includes a small one on dronabinol, a kamagra sex human-made version of medical THC.

Early research shows it might help with obstructive sleep apnea. But “at this point, we do not recommend the use of cannabis products for treatment of sleep apnea or other sleep disorders,” Kolla says.Ryan Vandrey, PhD, kamagra sex professor of psychiatry and behavioral sciences at Johns Hopkins University in Baltimoe, looks at how cannabis use affects sleep. He says there’s evidence that THC can help you fall asleep faster in the short-term. But “there’s a big gap in our knowledge” for how cannabis affects overall sleep quality long-term or if it can help people kamagra sex with sleep disorders.Possible BenefitsMichelle Sexton, ND (naturopathic doctor), assistant adjunct professor in the department of anesthesiology at the University of California, San Diego, helps people use cannabis to manage certain health conditions.

She says those who use THC to ease pain often report longer sleep time. €œThey’re not waking as much,” she says. Sexton sees some real-world kamagra sex benefits from THC products. But when it comes to cannabis research on sleep, “the body of literature is pretty small.”There’s some evidence that nabilone -- another human-made form of cannabis -- might help ease sleep problems related to posttraumatic stress disorder (PTSD).

Vandrey says people with PTSD often say kamagra sex they have fewer nightmares when they use cannabis. €œA lot of folks report not remembering dreams,” he says.A lot more research is needed to know if CBD can help with sleep. Vandrey says people who use it to manage other health conditions -- kamagra sex anxiety, pain, epilepsy -- often say their sleep gets better. But he says we don’t know if that’s from the CBD itself or because the compound helps in other ways.“We can try to piece together a story,” Vandrey says.

€œBut it’s really an incomplete picture at this point.”Risks of Using CannabisYour brain and body get used to the chemicals in cannabis or other drugs. You’ll have to use a higher dose to kamagra sex get the same effects. With repeated use, cannabis might not help you sleep as well, or you might find it hard to snooze on your own. €œWhat commonly happens is people get into a pattern of using cannabis -- whether it’s a high THC or high CBD hemp product -- on a daily basis for an extended kamagra sex period of time,” Vandrey says.

€œThen, when they go one night without it, they can’t sleep.”You’re not likely to overdose on THC or CBD, but here are some things to think about:Withdrawal. Long-term cannabis use can cause kamagra sex sleep problems when you try to quit. Vandrey says that includes insomnia and the return of vivid dreams or nightmares.Dizziness or balance problems. If you have to get up to pee at night, Sexton says to give yourself a minute to see if you feel stable.

If you have a walking aid, make sure kamagra sex you use it.Trouble thinking clearly. Heavy cannabis use is linked to problems with memory, learning, and attention.Health problems. Smoking any kamagra sex substance can hurt your lungs, heart, or blood vessels.Substance misuse. Cannabis is less addictive than alcohol or opioids.

But people who use kamagra sex it every day might get a cannabis use disorder. Tell your doctor if you want to stop but can’t. They’ll help you quit. Don’t use cannabis kamagra sex products if you’re pregnant or breastfeeding.

The drug could affect your baby.Is CBD Safe?. Kolla says it’s OK to use CBD if you kamagra sex think it helps your sleep. He says there isn’t any data to show that it’s harmful. But keep in mind these products aren’t regulated kamagra sex by the FDA.

There’s no way to know exactly what you’re getting. €œA lot of times, CBD can be contaminated with THC and there are potentials for drug interactions,” Kolla says.Vandrey says CBD can interact with multiple biological systems in the body. But he says there’s no research to know how long-term kamagra sex use will affect those systems. Until we know more, “keep use of these products controlled in some way,” he says.

€œYou use them for a couple of weeks and then you stop.”How to Use CannabisThere isn’t an official kamagra sex “dose” that works for everyone. Always read the product label for instructions. Even better, talk to a health care professional kamagra sex before you try THC or CBD. Tell them if you have other health problems or you take any other medication.

Sexton doesn’t suggest CBD as a sleep aid. She says kamagra sex it can have an “alerting” effect for some people. Here are some of her tips for how and when to use THC:Look for “indica” on the label. There isn’t kamagra sex one “nighttime” strain.

You’ll need to try different kinds to see what works best for you. Though, she says something labeled indica might be more sedating.Start with a low dose. Sexton says a 2-milligram dose is a good place to kamagra sex start. If you’re new to THC, you might want to go lower.

More might give you unwanted side kamagra sex effects. €œYou might wake up in the middle of the night paranoid with your mind racing,” Sexton says.Use oral THC. Drop it in the back of your mouth and kamagra sex swallow. €œI typically stick with the oral dose because of how long it lasts, and it comes on more slowly,” she says.The effects kick in after 1 to 3 hours, she says, and could last for 6 to 8 hours.

If you try a dose that doesn’t help, “wait it out.” Sexton says you can raise your dose by 50% the next night.If you have trouble staying asleep. Take an oral dose right kamagra sex as your “head hits the pillow.”If you have trouble falling asleep. Take an oral dose 1 to 2 hours before bed.Don’t go above 10 milligrams. A larger amount might raise your odds kamagra sex of poor sleep.

€œWe don’t know if (THC) is disrupting sleep architecture at those higher doses,” Sexton says.Talk to a DoctorAsk about nondrug ways to get a good night’s rest. €œMy sleep expert colleagues will always say behavioral treatments are kamagra sex superior to pharmacological treatments,” Vandrey says.Sexton urges good sleep hygiene. But she also tries to find any hidden problems. Here are some questions she asks:Do you exercise at 8 p.m.?.

Do you drink green tea with dinner? kamagra sex. Do you take your B vitamins at night?. Are you stressed kamagra sex or anxious?. Is your sleep trouble linked to hormonal changes?.

No detail is too small and could help your doctor figure out kamagra sex what’s triggering your sleep issues.Emergency department visit rates because of an opioid overdose increased by 28.5% across the U.S. In 2020, compared to 2018 and 2019, recent Mayo Clinic research finds. Emergency visits overall decreased by 14% last year, while visits because of an opioid overdose increased by 10.5%. The result kamagra sex.

Opioid overdoses were responsible for 0.32 out of 100 visits, or 1 in every 313 visits, which is up from 0.25, or 1 in every 400 visits, the previous two years.This trend is supported by preliminary data recently released by the Centers for Disease Control and Prevention (CDC), which recorded more than 93,000 opioid overdose deaths in 2020. That's a 29.4% increase from the year prior and the most opioid overdose deaths every recorded in the U.S.The research was published in the Annals of Emergency Medicine and was presented in June kamagra sex at the AcademyHealth annual research meeting. The research also was presented at the Society for Academic Emergency Medicine's conference, where it was selected for a plenary session."erectile dysfunction treatment, and the disruptions in every part of our social and work lives, made this situation even harder by increasing the risk of opioid misuse and relapse because people were separated from their social support and normal routines," says Molly Jeffery, Ph.D., a researcher in the Mayo Clinic Robert D. And Patricia kamagra sex E.

Kern Center for the Science of Health Care Delivery and senior author. "While institutions across the U.S. Are keenly aware that opioid misuse is a major health concern, this shows that there is more work to be done, and it provides an opportunity for institutions and policymakers to expand evidence-based treatments and resources."Over 70% of drug overdose deaths in 2019 involved kamagra sex an opioid, according to the CDC, though trends were leveling off before the erectile dysfunction treatment kamagra. Since then, that trend has reversed significantly, data are showing.The research team studied visits to 25 emergency departments in six states -- Alabama, Colorado, Connecticut, North Carolina, Massachusetts and Rhode Island -- from January 2018 through December 2020.

Opioid-related overdose visits increased to kamagra sex 3,486 in 2020 from 3,285 and 3,020 in 2019 and 2018, respectively. Previous research by this team found an immediate and significant decrease in emergency department visits during the first few months of the erectile dysfunction treatment kamagra, a trend that continued throughout 2020. advertisement Despite the increase in opioid-related visits, the researchers say evidence suggests the percentage of people who experience an overdose but choose not to visit the emergency department is likely increasing, suggesting overdose rates may be even higher."In the absence of comprehensive, real-time national surveillance data, our results offer evidence that the increases in nonfatal opioid overdose rates are not isolated to specific communities," the researchers kamagra sex wrote.Dr. Jeffery says treatments for opioid misuse, such as buprenorphine and methadone, need to be more accessible, as does naloxone, an opioid overdose reversal drug.

She says, however, it's a good sign that telemedicine access for psychiatric care increased during the kamagra and has remained high."We think this may be an important way to increase the accessibility of care for many people with opioid misuse disorder or addiction," Dr. Jeffery says.The kamagra sex lead author is William Soares, M.D., University of Massachusetts Medical School-Baystate. Co-authors are from the Yale School of Medicine, The University of Alabama at Birmingham, the University of North Carolina School of Medicine, the Warren Alpert Medical School of Brown University, and the University of Colorado School of Medicine.The research was supported by the National Institute on Drug Abuse, of the National Institutes of Health.The research also was supported by the Mayo Clinic Robert D. And Patricia E kamagra sex.

Kern Center for the Science of Health Care Delivery. The center seeks to discover new ways kamagra sex to improve health. Translate those discoveries into evidence-based, actionable treatments, processes and procedures. And apply this new knowledge to improve care for patients everywhere.

Story Source kamagra sex. Materials provided by Mayo Clinic. Original written kamagra sex by Adam Harringa. Note.

Content may be edited for style and length.Using kamagra sex advanced imaging technology, Mayo Clinic scientists have provided an unprecedented understanding of the BRCA1-BARD1 protein complex, which is often mutated in patients with breast or ovarian cancer. Their paper, published in Nature, identifies aspects of how BRCA1-BARD1 functions, supporting future translational research, cancer prevention efforts and drug development."BRCA1-BARD1 is important for DNA repair. It has direct relevance to cancer because hundreds of mutations in the BRCA1 and BARD1 genes have been identified in cancer patients," says Georges Mer, Ph.D., a Mayo Clinic structural biologist and biochemist who is the lead author of the paper. "But no one knows if these kamagra sex mutations, or variants of unknown significance, are cancer-predisposing or not because we do not know whether the variants are located in a region of BRCA1-BARD1 that is important for function.

Now because we can see how BRCA1-BARD1 works, we have a good idea of what regions of BRCA1-BARD1 are important for function."In a cell, the complex of DNA and histone proteins are complexed into what's called chromatin, and packaged into bundles called nucleosomes. DNA damage response proteins need kamagra sex to access chromatin to repair damaged DNA. BRCA1-BARD1 contributes to fixing broken DNA strands, which helps in the maintenance and survival of cells. But it is also a function that could possibly be blocked or inactivated if this is a strategy a cancer cell uses to survive chemotherapy.Cryo-electron microscopy and nuclear magnetic resonance kamagra sex spectroscopy"We used two techniques -- cryo-electron microscopy and nuclear magnetic resonance spectroscopy -- to understand at near-atomic resolution how BRCA1-BARD1 associates with the nucleosome, the repeating unit of chromatin, and how BRCA1-BARD1 modifies chromatin," explains Dr.

Mer.In cryo-electron microscopy, purified BRCA1-BARD1 bound to nucleosomes, together referred to as macromolecules, are flash-frozen then imaged using an electron microscope. The macromolecules are oriented in various ways within the sample so a computer program evaluates all the orientation data to create a 3D structure. Dr. Mer and his team also examined BRCA1-BARD1 nucleosome complexes with nuclear magnetic resonance spectroscopy, which uses a strong magnet to probe the relative positions of atoms within macromolecules.

Using these imaging tools, the scientists could visualize BRCA1-BARD1 in action and uncover a new function of the complex."We showed how BRCA1-BARD1 attaches ubiquitin to the nucleosome, but we also determined that BRCA1-BARD1 recognizes ubiquitin already attached to the nucleosome, which serves as a signal for broken DNA," says Dr. Mer. "We discovered an unexpected cross-talk by which ubiquitin recognition by BRCA1-BARD1 enhances its ubiquitin attachment activity, and this helps us better understand how BRCA1-BARD1 performs its function."The researchers created a video from the cryo-electron microscopy data to show where the protein complex interacts with the nucleosome [see link below].From discovery science to patient careDr. Mer and his team expect that high-resolution images of BRCA1-BARD1 can help guide patient care and future treatment of cancer in two ways.

Classifying variants of unknown significance and directing drug development with more accuracy."With these 3D structures, we should be able to convert several variants of unknown significance to likely cancer-predisposing variants," says Dr. Mer. "This work is also expected to have an impact on drug development in the long term because the 3D structures of BRCA1-BARD1 in complex with the nucleosome we generated may help in the design of small molecules that could, for example, inactivate BRCA1-BARD1."In addition to Dr. Mer, other authors on the paper are Qi Hu, Ph.D..

Maria Victoria Botuyan, Ph.D.. Debiao Zhao, Ph.D.. Gaofeng Cui, Ph.D.. And Elie Mer.

This research was funded by the National Institutes of Health, Mayo Clinic Cancer Center, Mayo Clinic Center for Biomedical Discovery, and the Ovarian Cancer Research Alliance, and was made possible through cryo-electron microscopy and nuclear magnetic resonance instrumentation at the Pacific Northwest Center for Cryo-EM and Mayo Clinic, respectively. Story Source. Materials provided by Mayo Clinic. Original written by Sara Tiner.

Note. Content may be edited for style and length.Though the two main histological types of breast cancer -- lobular and ductal -- are treated with the same hormonal therapies, women with lobular breast cancer often have recurrence or metastasis of the disease several years after their initial treatment.In an attempt to find out why the long-term outcomes are poorer for patients with lobular breast cancer -- which affects some 40,000 women a year -- University of Colorado Cancer Center member Matthew Sikora, PhD, began looking at the role of the protein MDC1 in tumor cells."This is a protein that's normally involved in DNA repair, but it seems to have some new function in lobular cancer cells," Sikora says. "It's now required for estrogen receptor activity."MDC1 and estrogenDuctal cancer and lobular cancer cells both use the hormone estrogen to grow, Sikora explains, and the antiestrogen drug tamoxifen typically blocks estrogen in the tumor cell, thwarting that growth. In a paper published in May in the journal Molecular Cancer Research, however, Sikora and his fellow researchers from the CU School of Medicine examined how in lobular cancer cells, the MDC1 protein allows cells to use tamoxifen as a weak estrogen, causing them to keep growing, albeit at a lesser rate."We think this MDC1 protein may be what influences how lobular cells respond to estrogen in the first place," Sikora says.

"Back in the 1980s, when women got hormone replacement therapy and there was an uptick in breast cancer risk, most of that was lobular. It's this idea that these cells are just seeing anything that is estrogen-like differently. Not only is MDC1 possibly promoting this resistance to tamoxifen because of how it changes the way estrogen receptors work, but it may be playing a role in how estrogen works in the tumor cell."Looking for new treatmentsBecause lobular tumors often metastasize to the abdomen, GI tract, and ovaries, they can be harder to detect, Sikora says. This makes it all the more imperative to figure out a novel way to treat this type of tumor.

Based on his initial research, Sikora is now looking at what other proteins work with MDC1 to promote tumor growth -- and novel ways to stop that growth from happening."The way MDC1 normally works in DNA repair is like a scaffold. It sits on damaged sites and then recruits in other repair proteins," he says. "It's plausible that it would do something similar for estrogen receptor -- instead of repair proteins, it might bring in partners that open and close DNA to let genes turn on and off. We have to figure out if there are other partners involved, if there's a bigger complex that makes that process possible."With funding from the American Cancer Society, Sikora and his research partners will spend the next few years identifying those partners and how to combat them.

They also plan to explore how the role of MDC1 in DNA repair changes in lobular cancer cells, and how that might reveal other vulnerabilities. Ultimately, he hopes the research will lead to better treatment for lobular cancer patients -- treatment that reduces the risk of metastases and recurrences years down the road."Right now, even though patients are differentially diagnosed with either lobular or ductal breast cancer, there are few different therapy decisions, despite what we're learning about how outcomes are different," Sikora says. "For a patient with lobular cancer, ideally we could identify, using gene-expression signatures, whether this estrogen receptor-MDC1 partnership is active in the tumor. Then we can treat them accordingly.

That's the long-term goal." Story Source. Materials provided by University of Colorado Anschutz Medical Campus. Original written by Greg Glasgow. Note.

Content may be edited for style and length.For 70 years, clinicians thought they knew the shape of tuberculosis granulomas in the lungs of patients. Histology -- the study of microscopic structures in thin slices of lung tissue in the 1940s and 1950s -- showed round features, and researchers intuitively assumed that meant the granulomas were spherical or ovoid.That long-lived paradigm is now shown to be wrong, in a study by researchers at the University of Alabama at Birmingham and the Africa Health Research Institute, or AHRI, Durban, KwaZulu-Natal, South Africa. The historical histology, essentially, was a two-dimensional look at structures, similar to cutting a very thin slice through a tree branch, a slice that would look round or oval.The new research has created a three-dimensional view of diseased lung tissue from tuberculosis patients, using micro-computed tomography, or microCT. This revealed that the larger granulomas were anything but round -- rather they had complex, branched shapes.

One granuloma looked somewhat like a ginger root, another like a cluster of early buds on a cherry tree, before the blossoms appear. The tuberculosis granulomas showed marked heterogeneity in shape, volume and number in the lung sections. (See link to study below for videos of the three-dimensional views.)A granuloma is an aggregation of immune cells summoned in response to chronic inflammation. In tuberculosis, the granulomas are often necrotic, meaning they are a mass of formless dead debris.Researchers led by Adrie Steyn, Ph.D., a UAB professor of microbiology and a member of the AHRI, used microCT, histology and immunohistochemistry to construct three-dimensional views of necrotic granulomas, and also vasculature and airways.

This yielded an unanticipated insight into the spatial organization of tuberculosis granulomas in relation to airways and vasculature."Unlike depictions of granulomas as simple spherical structures," Steyn said, "human necrotic granulomas exhibit complex, cylindrical, branched morphologies that are connected to the airways and shaped by the bronchi."Steyn says these visualizations have three impacts. They highlight the likelihood that a single structurally complex lesion could be mistakenly viewed as multiple independent lesions when evaluated in two dimensions. Second, the lack of vascularization within obstructed bronchi establishes a paradigm for anti-mycobacterial drug tolerance, since the microbes are protected from a full delivery of blood-borne bactericidal drugs. Third, the results suggest that a bronchogenic spread of the Mycobacterium tuberculosis pathogen re-seeds the lung.

advertisement "Hence, our findings provide a rationale for considering aerosolized anti-tuberculosis drug delivery," Steyn said. "This approach could allow delivery of high, local concentrations of drugs directly into granulomas or cavities in the lung, possibly reducing treatment times, systemic dosing and toxicity." s by the Mycobacterium tuberculosis bacterium kill about 1.3 million people a year.Steyn and colleagues say, to their knowledge, this is the first three-dimensional description of granulomas, airways and vasculature for any bacterial pulmonary pathogen.Infected human lung tissue is readily available for study in Durban because that part of Africa is an epicenter for tuberculosis. The Inkosi Albert Luthuli Central Hospital, not far from AHRI, does resection surgeries to remove diseased lobes from tuberculosis patients. MicroCT is similar to the common medical CAT scans but has a much finer resolution.

The researchers used resolutions as small as 12 microns, which is about the thickness of a sheet of plastic kitchen wrap. Research leader Steyn maintains labs at UAB and the AHRI. He lives in Durban and visits UAB about six times a year.The study, "µCT Analysis of the Human Tuberculous Lung Reveals Remarkable Heterogeneity in 3D Granuloma Morphology," was published in the American Journal of Respiratory and Critical Care Medicine. The journal also published an editorial on the Steyn study.Co-authors with Steyn are Gordon Wells, Kievershen Nargan and Kapongo Lumamba, AHRI.

Joel N. Glasgow, UAB Department of Microbiology. Rajhmun Madansein and Kameel Maharaj, Inkosi Albert Luthuli Central Hospital and University of KwaZulu-Natal, Durban, South Africa. Robert L.

Hunter, University of Texas Health Sciences Center at Houston. Threnesan Naidoo, Inkosi Albert Luthuli Central Hospital. And Llelani Coetzer, Stephan Le Roux and Anton du Plessis, Stellenbosch University, South Africa.Support came from National Institutes of Health grants Al111940, AI134810, AI137043, AI138280 and A127182. A Bill and Melinda Gates Foundation Award.

And pilot funds from the UAB Center for AIDS Research, the UAB Center for Free Radical Biology, and the Infectious Diseases and Global Health and treatments Initiative. Support also came CRDF Global, the South African Medical Research Council and a South Africa National Research Foundation BRICS Multilateral grant..

Getting diagnosed with depression Cialis 20mg price brings kamagra online uk up different emotions for different people. After your doctor or mental health provider gives you the news, it’s a good idea to reach out for support from family, friends, or others in your community. They may be able to help you process what you’re feeling.“For some people kamagra online uk there’s relief. Here’s an answer that explains what’s going on with you.

It’s a medical condition and it’s highly treatable,” says Ashley J kamagra online uk. Smith, PhD, a licensed clinical psychologist in Kansas City, MO, and co-founder of the psychological center Peak Mind.Other people struggle with the diagnosis, she says. You might think. €œâ€˜I have kamagra online uk depression.

What does that mean about me?. Am I flawed or kamagra online uk broken?. €™â€Learning you have a mood disorder can be tough to hear. You could even feel ashamed if your family kamagra online uk or community dismisses mental health conditions, says Jameca Cooper, PhD, a counseling psychologist in St.

Louis and president and clinical director of Emergence Psychological Services. €œA lot of my patients talk about how their families don’t really believe in mental health issues like depression or anxiety,” Cooper says. €œSometimes they refer to baby boomer parents that say, ‘Just kamagra online uk suck it up. Get over it.

Just get kamagra online uk enough rest. Just work harder.’ ... A lot of people’s families see mental health as a weakness.”Some people come from kamagra online uk communities that don’t believe in mental health diagnoses, she adds. €œIn their countries of origin there is no such thing as anxiety or depression or schizophrenia.

They might call it something else, and they might lump all of them together.”Smith, who’s a member of the Anxiety &. Depression Association of America, recommends educating yourself and your loved ones about depression by kamagra online uk checking out reputable sources, like the ADAA’s website. €œThere [are] myths out there, and you need to understand. €˜Here’s the actual science, here’s what we actually know about it.’ And that can help dispel some of those myths and criticisms,” kamagra online uk Smith says.

€œâ€˜We have to work hard to help people understand that mental illness has nothing to do with your character,” she adds. €œIt has nothing to do with your value as a kamagra online uk human, your intelligence. It’s neurobiological.”Who to Ask for SupportIf your family and close friends accept that mental health conditions are serious health conditions, talk to them about your depression diagnosis, Cooper and Smith say.“We need strong supports. We need healthy relationships.

And you need that more than ever when you’re kamagra online uk experiencing depression,” Smith says. €œBeing open with the people in your life helps maintain those connections, which is a protective factor.”A candid conversation could also help them understand what you’ve been going through if depression has been making you irritable, negative, or uncommunicative, she says. That way, they can kamagra online uk give you encouragement and help you stick to your treatment.Tell your loved ones what kind of support you need, Cooper says. Try to be specific.

Maybe you just need understanding and patience, rather than frequent phone calls to check in on you kamagra online uk. Or maybe you’d appreciate an occasional hand with certain responsibilities, like help making meals or someone to pick the kids up from school. If you’ve heard your loved ones mock or disregard mental health issues in the past, you can still try to educate them about your diagnosis. But you might want to look elsewhere for guidance and understanding, Cooper says.You can connect with people kamagra online uk outside of your family and friends, too.

A local or virtual support group for depression is one good option. There, you can meet people who understand what kamagra online uk you’re going through, and they may be able to give you tips that helped them. A support group can be especially helpful if other things in your life are playing a role in your depression, like a serious health condition or ongoing grief from a personal loss, Cooper says.If you’re religious, you can also make your faith a part of your healing process. For example, some churches kamagra online uk offer support groups and different types of counseling, Cooper says.Getting support specifically for depression is key, but you can benefit from indirect emotional boosts, too.

For example, you could volunteer for a cause that makes you feel good, Smith says. €œWhen you’re finding a sense of meaning and purpose, when you’re engaging with other people, when you’re doing activities that matter, those can help actually address some symptoms of depression,” she says. Physical activity is a great way to help kamagra online uk take charge of depression, she adds. €œA gym or exercise can also provide that sense of community and of support while also getting that exercise in.”As you come to grips with your diagnosis and find emotional support, work closely with your doctor oror mental health provider.

Ask them which treatments kamagra online uk and lifestyle changes might help you feel your best. €œThere’s a lot of different pathways that can lead to depression,” Smith says. €œSo that also means we have a lot of different treatment options that can work.”July 28, 2201 -- kamagra online uk About half of adults in the United States say that they would be uncomfortable seeing a doctor who had not been vaccinated against erectile dysfunction treatment, according to a recent WebMD/Medscape poll. In the survey, 54% of the 687 respondents said that they would be “not at all comfortable” seeing an unvaccinated doctor, with 9% selecting the “somewhat comfortable” option, while more than a third (37%) said they would be “very comfortable” in that situation.

Women and men largely agreed on their level of comfort. 58% of women and 57% of men said not at all, 7% of women and 10% of men said somewhat, and 35% of women and 33% of men said vaccination status did not matter to them, based on the responses received during data collection on kamagra online uk July 8-9, 2021. As with so many things American these days, however, there are some significant differences hiding in those findings. Age differences, for example, played a major kamagra online uk role in the results, with 64% of those ages 45 years and older saying they were not at all comfortable, vs.

46% of those under age 45. Respondents living in the West were most likely to express their comfort with nonvaccinated doctors (46%), and those in kamagra online uk the Northeast were least likely (26%), with the Midwest (35%) and the South (38%) falling in between. Scenarios. Should Providers Be Punished?.

The survey also included a question about whether health care providers should be punished if they kamagra online uk expose others to erectile dysfunction treatment through various scenarios while at work. The scenario voted worst was a clinician who had erectile dysfunction treatment but continued to work without using personal protective equipment (PPE). Eighty-two percent of kamagra online uk respondents agreed that was worthy of punishment. A clinician who knew they were infected but continued to work while wearing PPE was the only other scenario where more than half of the respondents supported punishment (53%).

Doctors, physician assistants, nurses, pharmacists, and other health care providers were kamagra online uk also asked similar questions. That poll surveyed 2,498 professionals and was conducted July 7-18. That group came to a similar conclusion. More than 90% said kamagra online uk that the clinician who knew they were infected but kept working without PPE should be punished.

The opinions in that survey differed somewhat after that, both from the patient poll and between the clinician groups. None of the other scenarios reached 50% support for punishment among the doctors, but 51% of nurses and 55% of other providers wanted to punish a clinician known to kamagra online uk have erectile dysfunction treatment who infected a vulnerable patient. WebMD Health News Sources WebMD/Medscape polls, July 8-9, 2021, July 7-18, 2021. © 2021 WebMD, LLC kamagra online uk.

All rights reserved.SOURCES. Annie Miller, behavioral sleep medicine therapist, DC Metro Sleep and Psychotherapy. Mayo Clinic kamagra online uk. €œInsomnia treatment.

Cognitive behavioral therapy instead of kamagra online uk sleeping pills.” Kaur, H. Spurling, B. Bollu, P kamagra online uk. Chronic Insomnia, StatPearls Publishing, 2021.

Sleep Foundation. €œLight Therapy for Insomnia Sufferers,” “Sleep Hygiene,” “Light and Sleep,” “Mental Health and Sleep.” Stanford kamagra online uk Health Care. €œStimulus Control and CBTI.”If you’re one of the millions of people who have trouble sleeping, you may have considered a cannabis compound, such as CBD. Some say cannabis compounds are helpful, but more research is kamagra online uk needed.

And they might not be legal, depending on where you live. Look up the laws to know what’s allowed.What Does the kamagra online uk Research Say About Cannabis?. Also known as marijuana, there’s growing interest in the health benefits of cannabis, specifically cannabis compounds. Two cannabinoids that get a lot of attention are:Tetrahydrocannabinol (THC).

The compound in kamagra online uk cannabis that makes you feel high. Human-made versions are used to ease nausea and vomiting from cancer treatment.Cannabidiol (CBD). A compound in cannabis kamagra online uk said to have anti-inflammatory and anti-seizure properties. It does not make you feel high.Research results on cannabis and sleep are mixed.

So far, kamagra online uk there haven’t been many controlled studies to show that THC, CBD, or a combination of both can boost sleep quality, says Bhanuprakash (Bhanu) Kolla, MD. He’s an associate professor of psychiatry and psychology and a consultant for Mayo Clinic’s Center for Sleep Medicine in Rochester, MN. But some studies show promise. That includes a kamagra online uk small one on dronabinol, a human-made version of medical THC.

Early research shows it might help with obstructive sleep apnea. But “at this point, we do not recommend the use of cannabis products for treatment of sleep apnea or other sleep disorders,” Kolla says.Ryan Vandrey, PhD, professor kamagra online uk of psychiatry and behavioral sciences at Johns Hopkins University in Baltimoe, looks at how cannabis use affects sleep. He says there’s evidence that THC can help you fall asleep faster in the short-term. But “there’s a big gap in our knowledge” for how cannabis affects overall sleep quality long-term or if it can help people kamagra online uk with sleep disorders.Possible BenefitsMichelle Sexton, ND (naturopathic doctor), assistant adjunct professor in the department of anesthesiology at the University of California, San Diego, helps people use cannabis to manage certain health conditions.

She says those who use THC to ease pain often report longer sleep time. €œThey’re not waking as much,” she says. Sexton sees some real-world benefits from kamagra online uk THC products. But when it comes to cannabis research on sleep, “the body of literature is pretty small.”There’s some evidence that nabilone -- another human-made form of cannabis -- might help ease sleep problems related to posttraumatic stress disorder (PTSD).

Vandrey says kamagra online uk people with PTSD often say they have fewer nightmares when they use cannabis. €œA lot of folks report not remembering dreams,” he says.A lot more research is needed to know if CBD can help with sleep. Vandrey says kamagra online uk people who use it to manage other health conditions -- anxiety, pain, epilepsy -- often say their sleep gets better. But he says we don’t know if that’s from the CBD itself or because the compound helps in other ways.“We can try to piece together a story,” Vandrey says.

€œBut it’s really an incomplete picture at this point.”Risks of Using CannabisYour brain and body get used to the chemicals in cannabis or other drugs. You’ll have kamagra online uk to use a higher dose to get the same effects. With repeated use, cannabis might not help you sleep as well, or you might find it hard to snooze on your own. €œWhat commonly happens is people get into a pattern of using cannabis -- kamagra online uk whether it’s a high THC or high CBD hemp product -- on a daily basis for an extended period of time,” Vandrey says.

€œThen, when they go one night without it, they can’t sleep.”You’re not likely to overdose on THC or CBD, but here are some things to think about:Withdrawal. Long-term cannabis use can kamagra online uk cause sleep problems when you try to quit. Vandrey says that includes insomnia and the return of vivid dreams or nightmares.Dizziness or balance problems. If you have to get up to pee at night, Sexton says to give yourself a minute to see if you feel stable.

If you have a walking aid, make sure you use it.Trouble thinking kamagra online uk clearly. Heavy cannabis use is linked to problems with memory, learning, and attention.Health problems. Smoking any substance can kamagra online uk hurt your lungs, heart, or blood vessels.Substance misuse. Cannabis is less addictive than alcohol or opioids.

But people who use kamagra online uk it every day might get a cannabis use disorder. Tell your doctor if you want to stop but can’t. They’ll help you quit. Don’t use kamagra online uk cannabis products if you’re pregnant or breastfeeding.

The drug could affect your baby.Is CBD Safe?. Kolla says it’s OK to kamagra online uk use CBD if you think it helps your sleep. He says there isn’t any data to show that it’s harmful. But keep in mind these products aren’t kamagra online uk regulated by the FDA.

There’s no way to know exactly what you’re getting. €œA lot of times, CBD can be contaminated with THC and there are potentials for drug interactions,” Kolla says.Vandrey says CBD can interact with multiple biological systems in the body. But he says there’s no research to know how long-term use will affect kamagra online uk those systems. Until we know more, “keep use of these products controlled in some way,” he says.

€œYou use them for a couple of weeks kamagra online uk and then you stop.”How to Use CannabisThere isn’t an official “dose” that works for everyone. Always read the product label for instructions. Even better, talk to a health care professional before kamagra online uk you try THC or CBD. Tell them if you have other health problems or you take any other medication.

Sexton doesn’t suggest CBD as a sleep aid. She says it kamagra online uk can have an “alerting” effect for some people. Here are some of her tips for how and when to use THC:Look for “indica” on the label. There isn’t kamagra online uk one “nighttime” strain.

You’ll need to try different kinds to see what works best for you. Though, she says something labeled indica might be more sedating.Start with a low dose. Sexton says a 2-milligram dose is a good place to start kamagra online uk. If you’re new to THC, you might want to go lower.

More might kamagra online uk give you unwanted side effects. €œYou might wake up in the middle of the night paranoid with your mind racing,” Sexton says.Use oral THC. Drop it in the back of your mouth kamagra online uk and swallow. €œI typically stick with the oral dose because of how long it lasts, and it comes on more slowly,” she says.The effects kick in after 1 to 3 hours, she says, and could last for 6 to 8 hours.

If you try a dose that doesn’t help, “wait it out.” Sexton says you can raise your dose by 50% the next night.If you have trouble staying asleep. Take an oral dose right as your kamagra online uk “head hits the pillow.”If you have trouble falling asleep. Take an oral dose 1 to 2 hours before bed.Don’t go above 10 milligrams. A larger amount might raise your kamagra online uk odds of poor sleep.

€œWe don’t know if (THC) is disrupting sleep architecture at those higher doses,” Sexton says.Talk to a DoctorAsk about nondrug ways to get a good night’s rest. €œMy sleep expert colleagues will always say behavioral treatments are superior to pharmacological kamagra online uk treatments,” Vandrey says.Sexton urges good sleep hygiene. But she also tries to find any hidden problems. Here are some questions she asks:Do you exercise at 8 p.m.?.

Do you kamagra online uk drink green tea with dinner?. Do you take your B vitamins at night?. Are you kamagra online uk stressed or anxious?. Is your sleep trouble linked to hormonal changes?.

No detail is too small and could help your doctor figure out what’s triggering your sleep issues.Emergency department visit rates because of an opioid overdose increased by kamagra online uk 28.5% across the U.S. In 2020, compared to 2018 and 2019, recent Mayo Clinic research finds. Emergency visits overall decreased by 14% last year, while visits because of an opioid overdose increased by 10.5%. The result kamagra online uk.

Opioid overdoses were responsible for 0.32 out of 100 visits, or 1 in every 313 visits, which is up from 0.25, or 1 in every 400 visits, the previous two years.This trend is supported by preliminary data recently released by the Centers for Disease Control and Prevention (CDC), which recorded more than 93,000 opioid overdose deaths in 2020. That's a 29.4% increase from the year prior and the most kamagra online uk opioid overdose deaths every recorded in the U.S.The research was published in the Annals of Emergency Medicine and was presented in June at the AcademyHealth annual research meeting. The research also was presented at the Society for Academic Emergency Medicine's conference, where it was selected for a plenary session."erectile dysfunction treatment, and the disruptions in every part of our social and work lives, made this situation even harder by increasing the risk of opioid misuse and relapse because people were separated from their social support and normal routines," says Molly Jeffery, Ph.D., a researcher in the Mayo Clinic Robert D. And Patricia kamagra online uk E.

Kern Center for the Science of Health Care Delivery and senior author. "While institutions across the U.S. Are keenly aware that opioid misuse is a major health concern, this shows kamagra online uk that there is more work to be done, and it provides an opportunity for institutions and policymakers to expand evidence-based treatments and resources."Over 70% of drug overdose deaths in 2019 involved an opioid, according to the CDC, though trends were leveling off before the erectile dysfunction treatment kamagra. Since then, that trend has reversed significantly, data are showing.The research team studied visits to 25 emergency departments in six states -- Alabama, Colorado, Connecticut, North Carolina, Massachusetts and Rhode Island -- from January 2018 through December 2020.

Opioid-related overdose visits increased to 3,486 in 2020 from 3,285 and 3,020 kamagra online uk in 2019 and 2018, respectively. Previous research by this team found an immediate and significant decrease in emergency department visits during the first few months of the erectile dysfunction treatment kamagra, a trend that continued throughout 2020. advertisement Despite the increase in opioid-related visits, the researchers say evidence suggests the percentage of people who experience an overdose but choose not to visit the emergency department is likely increasing, suggesting overdose rates may be even higher."In the absence of comprehensive, real-time national surveillance data, kamagra online uk our results offer evidence that the increases in nonfatal opioid overdose rates are not isolated to specific communities," the researchers wrote.Dr. Jeffery says treatments for opioid misuse, such as buprenorphine and methadone, need to be more accessible, as does naloxone, an opioid overdose reversal drug.

She says, however, it's a good sign that telemedicine access for psychiatric care increased during the kamagra and has remained high."We think this may be an important way to increase the accessibility of care for many people with opioid misuse disorder or addiction," Dr. Jeffery says.The lead author is kamagra online uk William Soares, M.D., University of Massachusetts Medical School-Baystate. Co-authors are from the Yale School of Medicine, The University of Alabama at Birmingham, the University of North Carolina School of Medicine, the Warren Alpert Medical School of Brown University, and the University of Colorado School of Medicine.The research was supported by the National Institute on Drug Abuse, of the National Institutes of Health.The research also was supported by the Mayo Clinic Robert D. And Patricia E kamagra online uk.

Kern Center for the Science of Health Care Delivery. The center seeks to discover new ways to improve kamagra online uk health. Translate those discoveries into evidence-based, actionable treatments, processes and procedures. And apply this new knowledge to improve care for patients everywhere.

Story Source kamagra online uk. Materials provided by Mayo Clinic. Original written by Adam Harringa kamagra online uk. Note.

Content may be edited for style and length.Using advanced imaging technology, Mayo Clinic scientists have provided an unprecedented understanding of the BRCA1-BARD1 protein complex, which is often kamagra online uk mutated in patients with breast or ovarian cancer. Their paper, published in Nature, identifies aspects of how BRCA1-BARD1 functions, supporting future translational research, cancer prevention efforts and drug development."BRCA1-BARD1 is important for DNA repair. It has direct relevance to cancer because hundreds of mutations in the BRCA1 and BARD1 genes have been identified in cancer patients," says Georges Mer, Ph.D., a Mayo Clinic structural biologist and biochemist who is the lead author of the paper. "But no one knows if these mutations, or variants of unknown significance, are cancer-predisposing or not because we do not know whether the variants are located in a region of BRCA1-BARD1 that is important kamagra online uk for function.

Now because we can see how BRCA1-BARD1 works, we have a good idea of what regions of BRCA1-BARD1 are important for function."In a cell, the complex of DNA and histone proteins are complexed into what's called chromatin, and packaged into bundles called nucleosomes. DNA damage response proteins kamagra online uk need to access chromatin to repair damaged DNA. BRCA1-BARD1 contributes to fixing broken DNA strands, which helps in the maintenance and survival of cells. But it is also a function that could possibly be blocked or inactivated if this is a strategy a cancer cell uses to survive chemotherapy.Cryo-electron microscopy and nuclear magnetic resonance spectroscopy"We used two techniques -- cryo-electron microscopy and nuclear magnetic resonance spectroscopy -- to understand at near-atomic resolution how BRCA1-BARD1 associates with the nucleosome, kamagra online uk the repeating unit of chromatin, and how BRCA1-BARD1 modifies chromatin," explains Dr.

Mer.In cryo-electron microscopy, purified BRCA1-BARD1 bound to nucleosomes, together referred to as macromolecules, are flash-frozen then imaged using an electron microscope. The macromolecules are oriented in various ways within the sample so a computer program evaluates all the orientation data to create a 3D structure. Dr. Mer and his team also examined BRCA1-BARD1 nucleosome complexes with nuclear magnetic resonance spectroscopy, which uses a strong magnet to probe the relative positions of atoms within macromolecules.

Using these imaging tools, the scientists could visualize BRCA1-BARD1 in action and uncover a new function of the complex."We showed how BRCA1-BARD1 attaches ubiquitin to the nucleosome, but we also determined that BRCA1-BARD1 recognizes ubiquitin already attached to the nucleosome, which serves as a signal for broken DNA," says Dr. Mer. "We discovered an unexpected cross-talk by which ubiquitin recognition by BRCA1-BARD1 enhances its ubiquitin attachment activity, and this helps us better understand how BRCA1-BARD1 performs its function."The researchers created a video from the cryo-electron microscopy data to show where the protein complex interacts with the nucleosome [see link below].From discovery science to patient careDr. Mer and his team expect that high-resolution images of BRCA1-BARD1 can help guide patient care and future treatment of cancer in two ways.

Classifying variants of unknown significance and directing drug development with more accuracy."With these 3D structures, we should be able to convert several variants of unknown significance to likely cancer-predisposing variants," says Dr. Mer. "This work is also expected to have an impact on drug development in the long term because the 3D structures of BRCA1-BARD1 in complex with the nucleosome we generated may help in the design of small molecules that could, for example, inactivate BRCA1-BARD1."In addition to Dr. Mer, other authors on the paper are Qi Hu, Ph.D..

Maria Victoria Botuyan, Ph.D.. Debiao Zhao, Ph.D.. Gaofeng Cui, Ph.D.. And Elie Mer.

This research was funded by the National Institutes of Health, Mayo Clinic Cancer Center, Mayo Clinic Center for Biomedical Discovery, and the Ovarian Cancer Research Alliance, and was made possible through cryo-electron microscopy and nuclear magnetic resonance instrumentation at the Pacific Northwest Center for Cryo-EM and Mayo Clinic, respectively. Story Source. Materials provided by Mayo Clinic. Original written by Sara Tiner.

Note. Content may be edited for style and length.Though the two main histological types of breast cancer -- lobular and ductal -- are treated with the same hormonal therapies, women with lobular breast cancer often have recurrence or metastasis of the disease several years after their initial treatment.In an attempt to find out why the long-term outcomes are poorer for patients with lobular breast cancer -- which affects some 40,000 women a year -- University of Colorado Cancer Center member Matthew Sikora, PhD, began looking at the role of the protein MDC1 in tumor cells."This is a protein that's normally involved in DNA repair, but it seems to have some new function in lobular cancer cells," Sikora says. "It's now required for estrogen receptor activity."MDC1 and estrogenDuctal cancer and lobular cancer cells both use the hormone estrogen to grow, Sikora explains, and the antiestrogen drug tamoxifen typically blocks estrogen in the tumor cell, thwarting that growth. In a paper published in May in the journal Molecular Cancer Research, however, Sikora and his fellow researchers from the CU School of Medicine examined how in lobular cancer cells, the MDC1 protein allows cells to use tamoxifen as a weak estrogen, causing them to keep growing, albeit at a lesser rate."We think this MDC1 protein may be what influences how lobular cells respond to estrogen in the first place," Sikora says.

"Back in the 1980s, when women got hormone replacement therapy and there was an uptick in breast cancer risk, most of that was lobular. It's this idea that these cells are just seeing anything that is estrogen-like differently. Not only is MDC1 possibly promoting this resistance to tamoxifen because of how it changes the way estrogen receptors work, but it may be playing a role in how estrogen works in the tumor cell."Looking for new treatmentsBecause lobular tumors often metastasize to the abdomen, GI tract, and ovaries, they can be harder to detect, Sikora says. This makes it all the more imperative to figure out a novel way to treat this type of tumor.

Based on his initial research, Sikora is now looking at what other proteins work with MDC1 to promote tumor growth -- and novel ways to stop that growth from happening."The way MDC1 normally works in DNA repair is like a scaffold. It sits on damaged sites and then recruits in other repair proteins," he says. "It's plausible that it would do something similar for estrogen receptor -- instead of repair proteins, it might bring in partners that open and close DNA to let genes turn on and off. We have to figure out if there are other partners involved, if there's a bigger complex that makes that process possible."With funding from the American Cancer Society, Sikora and his research partners will spend the next few years identifying those partners and how to combat them.

They also plan to explore how the role of MDC1 in DNA repair changes in lobular cancer cells, and how that might reveal other vulnerabilities. Ultimately, he hopes the research will lead to better treatment for lobular cancer patients -- treatment that reduces the risk of metastases and recurrences years down the road."Right now, even though patients are differentially diagnosed with either lobular or ductal breast cancer, there are few different therapy decisions, despite what we're learning about how outcomes are different," Sikora says. "For a patient with lobular cancer, ideally we could identify, using gene-expression signatures, whether this estrogen receptor-MDC1 partnership is active in the tumor. Then we can treat them accordingly.

That's the long-term goal." Story Source. Materials provided by University of Colorado Anschutz Medical Campus. Original written by Greg Glasgow. Note.

Content may be edited for style and length.For 70 years, clinicians thought they knew the shape of tuberculosis granulomas in the lungs of patients. Histology -- the study of microscopic structures in thin slices of lung tissue in the 1940s and 1950s -- showed round features, and researchers intuitively assumed that meant the granulomas were spherical or ovoid.That long-lived paradigm is now shown to be wrong, in a study by researchers at the University of Alabama at Birmingham and the Africa Health Research Institute, or AHRI, Durban, KwaZulu-Natal, South Africa. The historical histology, essentially, was a two-dimensional look at structures, similar to cutting a very thin slice through a tree branch, a slice that would look round or oval.The new research has created a three-dimensional view of diseased lung tissue from tuberculosis patients, using micro-computed tomography, or microCT. This revealed that the larger granulomas were anything but round -- rather they had complex, branched shapes.

One granuloma looked somewhat like a ginger root, another like a cluster of early buds on a cherry tree, before the blossoms appear. The tuberculosis granulomas showed marked heterogeneity in shape, volume and number in the lung sections. (See link to study below for videos of the three-dimensional views.)A granuloma is an aggregation of immune cells summoned in response to chronic inflammation. In tuberculosis, the granulomas are often necrotic, meaning they are a mass of formless dead debris.Researchers led by Adrie Steyn, Ph.D., a UAB professor of microbiology and a member of the AHRI, used microCT, histology and immunohistochemistry to construct three-dimensional views of necrotic granulomas, and also vasculature and airways.

This yielded an unanticipated insight into the spatial organization of tuberculosis granulomas in relation to airways and vasculature."Unlike depictions of granulomas as simple spherical structures," Steyn said, "human necrotic granulomas exhibit complex, cylindrical, branched morphologies that are connected to the airways and shaped by the bronchi."Steyn says these visualizations have three impacts. They highlight the likelihood that a single structurally complex lesion could be mistakenly viewed as multiple independent lesions when evaluated in two dimensions. Second, the lack of vascularization within obstructed bronchi establishes a paradigm for anti-mycobacterial drug tolerance, since the microbes are protected from a full delivery of blood-borne bactericidal drugs. Third, the results suggest that a bronchogenic spread of the Mycobacterium tuberculosis pathogen re-seeds the lung.

advertisement "Hence, our findings provide a rationale for considering aerosolized anti-tuberculosis drug delivery," Steyn said. "This approach could allow delivery of high, local concentrations of drugs directly into granulomas or cavities in the lung, possibly reducing treatment times, systemic dosing and toxicity." s by the Mycobacterium tuberculosis bacterium kill about 1.3 million people a year.Steyn and colleagues say, to their knowledge, this is the first three-dimensional description of granulomas, airways and vasculature for any bacterial pulmonary pathogen.Infected human lung tissue is readily available for study in Durban because that part of Africa is an epicenter for tuberculosis. The Inkosi Albert Luthuli Central Hospital, not far from AHRI, does resection surgeries to remove diseased lobes from tuberculosis patients. MicroCT is similar to the common medical CAT scans but has a much finer resolution.

The researchers used resolutions as small as 12 microns, which is about the thickness of a sheet of plastic kitchen wrap. Research leader Steyn maintains labs at UAB and the AHRI. He lives in Durban and visits UAB about six times a year.The study, "µCT Analysis of the Human Tuberculous Lung Reveals Remarkable Heterogeneity in 3D Granuloma Morphology," was published in the American Journal of Respiratory and Critical Care Medicine. The journal also published an editorial on the Steyn study.Co-authors with Steyn are Gordon Wells, Kievershen Nargan and Kapongo Lumamba, AHRI.

Joel N. Glasgow, UAB Department of Microbiology. Rajhmun Madansein and Kameel Maharaj, Inkosi Albert Luthuli Central Hospital and University of KwaZulu-Natal, Durban, South Africa. Robert L.

Hunter, University of Texas Health Sciences Center at Houston. Threnesan Naidoo, Inkosi Albert Luthuli Central Hospital. And Llelani Coetzer, Stephan Le Roux and Anton du Plessis, Stellenbosch University, South Africa.Support came from National Institutes of Health grants Al111940, AI134810, AI137043, AI138280 and A127182. A Bill and Melinda Gates Foundation Award.

And pilot funds from the UAB Center for AIDS Research, the UAB Center for Free Radical Biology, and the Infectious Diseases and Global Health and treatments Initiative. Support also came CRDF Global, the South African Medical Research Council and a South Africa National Research Foundation BRICS Multilateral grant..

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In this issue of BMJ How to buy ventolin Quality and Safety, Jorro-Barón and colleagues1 report the findings of a stepped-wedge cluster randomised trial (SW-CRT) to evaluate the implementation of kamagra oral jelly chemist warehouse the I-PASS handover system among six paediatric intensive care units (PICUs) at five Argentinian hospitals between July 2018 and May 2019. According to the authors, prior to the intervention kamagra oral jelly chemist warehouse there were complaints that handovers were ‘…lengthy, disorganized, …participants experienced problems with interruptions, distractions, and … senior professionals had problems accepting dissent’.Adverse events were assessed by two independent reviewers using the Global Assessment of Pediatric Patient Safety instrument. Study results demonstrated significantly improved handover compliance in the intervention group, validating Kirkpatrick Level 3 (behavioural change)2 effectiveness of the training initiative. Notably, however, on the primary outcome there were no differences between control and intervention groups regarding preventable adverse events per 1000 days of hospitalisation (control 60.4 (37.5–97.4) vs intervention 60.4 (33.2–109.9), p=0.998, kamagra oral jelly chemist warehouse risk ratio. 1.0 (0.74–1.34)).

Regarding balancing measures, there kamagra oral jelly chemist warehouse was no observed difference in the ‘full-shift’ handover duration (control 35.7 min (29.6–41.8). Intervention 34.7 min (26.5–42.1), p=0.490), although more time was spent on individual patient handovers in the intervention period (7.29 min (5.77–8.81). Control 5.96 kamagra oral jelly chemist warehouse min (4.69–7.23). P=0.001). From the provider perspective, preintervention and postintervention Agency for Healthcare Research and Quality (AHRQ) safety culture surveys did not show significant differences in their responses to communication-focused questions before and after the intervention.Thus, consistent with all previous studies, I-PASS was implemented successfully and handover quality improved.

However, is the lack of association of I-PASS implementation with clinical outcomes and adverse events in this study a concern?. To answer this question, it is necessary to review the origins of I-PASS more than a decade ago and its continually expanding evidence base.Healthcare has a handover problemHandovers are among the most vulnerable reoccurring processes in healthcare. In the AHRQ safety culture survey,3 the handovers and transitions of care domain is consistently among the lowest scoring, and handover and communication issues are among the most common cause of Joint Commission Sentinel Events and the subject of Joint Commission Sentinel Event Alert Issue 58.4 A study by CRICO Strategies found that communication issues were a factor in 30% of 23 658 malpractice claims filed from 2009 to 2013, accounting for $1.7 billion in incurred losses.5 The importance of handovers and care transitions for trainees is specifically discussed in a Clinical Learning Environment Review Issue Brief published by the Accreditation Council for Graduate Medical Education (ACGME),6 and Section VI.E.3 (Transitions of Care) of the ACGME Common Program Requirements (Residency) addresses the requirement for residents to be taught and to use structured handovers.7Both the numbers of handovers and handover-related problems have increased in contemporary practice because of greater patient complexity and the expanding number and types of providers involved in a typical patient’s care. Further, in teaching institutions, resident work-hour restrictions have resulted in the need for complex coverage schemes. Off-hours care is often provided by ‘cross-covering’, ‘float’ or ‘moonlighting’ practitioners who are responsible for numerous unfamiliar patients during their shifts, thus imposing an even greater need for effective handovers.

The net effect of all these changes may be inconsistent, fragmented care resulting from suboptimal handovers from one provider, service or hospital to another, with resulting medical errors (often of omission) and adverse events.Structured, standardised handoversThese serious vulnerabilities have led to pleas for more consistent, structured and standardised handovers.8–11 In addition to their use in routine shift-to-shift provider sign-off, these may be of particular value in the high-risk transfers of critically ill patients, such as from operating rooms to postoperative care units and ICUs12–16. Admissions to a surgery unit17. Management of trauma patients18–20. ICU to general ward transfers21 22. Night and weekend coverage of large services, many of whose patients are unfamiliar to the physician receiving the handover23–28.

And end-of-rotation resident transitions.29–31Given these considerations, standardised handovers, often involving mnemonic devices, have been widely advocated and studied in the past several decades, though many lack rigorous evaluation and few if any showed demonstrable associations with outcomes.32 33 Further, although some individual hospitals, units and services have implemented their own idiosyncratic handover systems, this does not solve the issue of handover inconsistency between different care delivery sites. A basic, common framework that could be customised to individual use cases would clearly be preferable.The I-PASS systemResponding to these concerns, the I-PASS Study Group was initiated in 2009 and the I-PASS Institute in 2016. Although numerous other systems are available, since its pilot studies a decade ago,34 35 I-PASS has emerged as the dominant system in healthcare for structured, standardised handovers. This system is specifically designed for healthcare applications. It is based on adult educational principles and simple to use.

It has been extensively validated in the peer-reviewed literature encompassing studies at multiple institutions in the USA and internationally34–40. And extensive training materials are available to assist programmes in implementation.39 41–45 Ideally, this system is implemented hospital-wide, which addresses the issue of cross-unit and cross-service transfers.I-PASS includes five major elements regarded as important for every handover—illness severity, patient summary, action list, situation awareness/contingency planning and synthesis by receiver. The first three of these elements are often included in non-structured handovers, although not necessarily in a specific sequence or format. The last two I-PASS elements—situational awareness/contingency planning and synthesis—have not historically been included in typical handover practice. The former assures that any anticipated problems are conveyed from the handover giver to the incoming provider and that appropriate responses to these issues are discussed.

Synthesis is closed-loop communication, with brief read-back of the handover information by the receiver to assure their accurate comprehension, followed by an opportunity for questions and discussion. This read-back of mission-critical communications is standard operating practice in other high-reliability settings such as aviation, the military and nuclear power. It is essential to establishing a shared mental model of the current state and any potential concerns. However, other than in I-PASS, it is quite uncommon in healthcare, with the potential exception of confirming verbal or telephonic orders.I-PASS validationIn an initial study of I-PASS handover implementation by residents on two general inpatient paediatric units at Boston Children’s Hospital,34 written handovers were more comprehensive and had fewer omissions of key data, and mean time spent on verbal handover sessions did not change significantly (32.3 min vs 33.2 min). Medical errors and adverse events were ascertained prospectively by research nurse reviewers and independent physician investigators.

Following I-PASS implementation, preventable adverse events decreased from 3.3 (95% CI 1.7 to 4.8) to 1.5 (95% CI 0.51 to 2.4) per 100 admissions (p=0.04), and medical error rates decreased significantly from 33.8 per 100 admissions (95% CI 27.3 to 40.3) to 18.3 per 100 admissions (95% CI 14.7 to 21.9. P<0.001). A commentary by Horwitz46 noted that this was ‘…by far the most comprehensive study of the direct effects of handoff interventions on outcomes within the context of existing work-hour regulations and is the first to demonstrate an associated significant decrease in medical errors on a large scale’, while also noting limitations including its uncontrolled, ‘before and after’ design, confounding by secular changes, Hawthorne effects and inability to blind the nurses collecting adverse event data.The more expansive, landmark I-PASS study was conducted by Starmer and colleagues37 among nine paediatric hospitals and 10 740 patient admissions between January 2011 and May 2013. Handover quality was evaluated, and medical errors and adverse events were ascertained by active surveillance, including on-site nurse review of medical records, orders, formal incident reports, nursing reports and daily medical error reports from residents. Independent physician investigators classified occurrences as adverse events, near misses or exclusions, and they subclassified adverse events as preventable or non-preventable.

Results revealed a 23% reduction in medical errors from the preintervention to the postintervention period (24.5 vs 18.8 per 100 admissions, p<0.001) and a 30% reduction in preventable adverse events (4.7 vs 3.3 events per 100 admissions, p<0.001). Inclusion of prespecified elements in written and verbal handovers increased significantly, and there was no significant change in handover time per patient (2.4 vs 2.5 min. P=0.55).Subsequent investigations in other institutions have replicated many of the findings of the original I-PASS studies, with higher postintervention inclusion rates of critical handover elements. Fewer mistakes or omissions. Greater provider satisfaction with handover organisation and information conveyed.

Unchanged or shorter handoff times. And decreased handover interruptions (probably reflecting greater attention to the importance of the handover process).36 40 47–50 In a mentored implementation study conducted in 2015–2016 among 16 hospitals (five community hospitals, 11 academic centres and multiple specialties), handover quality improved, and there was a provider-reported 27% reduction in adverse events.38 Among nurses at Boston Children’s Hospital, I-PASS implementation was associated with significant decreases in handover-related care failures.40In recognition of its achievements in improving healthcare quality, the I-PASS Study Group was awarded the 2016 John M Eisenberg Award for Patient Safety and Quality by the National Quality Forum and the Joint Commission.The challenge of linking handovers to clinical outcomes and eventsAlthough investigations from many centres, including the report of Jorro-Barrón and colleagues,1 have now confirmed that I-PASS can be readily assimilated and used by clinicians, most of these have either not rigorously assessed adverse events, medical errors and other clinical outcomes (Kirkpatrick Level 4 evaluation) or have failed to demonstrate significant postintervention improvements in these clinical outcomes. Why is this, and should current or potential I-PASS users be concerned?. With regard to the first question, there are practical considerations that complicate the rigorous study of clinical outcome improvements associated with I-PASS (or any other handover system). Notwithstanding the importance of effective communications, these are only one of many provider processes and hospital systems, not to mention the overall hospital quality and safety culture, that impact a patient’s clinical outcome.

In most hospitals, a diverse portfolio of quality and safety improvement initiatives are always being conducted. Disentangling and isolating the effects of any one specific intervention, such as I-PASS handovers, is challenging if not impossible. At a minimum, it requires real-time, prospective monitoring by trained nurse or physician reviewers as in the original I-PASS studies, a research design which realistically is unlikely to be reproduced. Ideally, the study design would also include blinding of the study period (control or intervention) and blinding of observers, the former of which is virtually impossible for this type of intervention.Further, if other provider processes and hospital systems are functioning at a high level, they may partially offset the impact of suboptimal communications and make it even more challenging to demonstrate significant improvements. The current study of Jorro-Barón and colleagues,1 which uses PICUs as the unit of analysis, illustrates this concept.

PICUs are typically among the most compulsive, detail-oriented units in any hospital, even if they may have nominally ‘non-standardized’ handovers.Study design. The SW-CRTIn an attempt to address the limitations of some previous studies, Parent and colleagues51 studied eight medical and surgical ICUs across two academic tertiary teaching hospitals using an SW-CRT design. Clinician self-assessment of having been inadequately prepared for their shift because of a poor-quality handoff decreased from 35 of 343 handoffs (10.2%) in the control arm to 53 of 740 handoffs (7.2%) postintervention (OR 0.19. 95% CI 0.03 to 0.74. P=0.03).

€˜Last-minute’, early morning order writing decreased, and handover duration increased but not significantly (+5.5 min. 95% CI 0.34 to 9.39. P=0.30). As in the current study of Jorro-Barón and colleagues,1 who also employed an SW-CRT, there were no associated changes in clinical outcomes such as ICU length of stay, duration of mechanical ventilation or necessity for reintubation. The authors comment that given high baseline quality of care in these ICUs, it was not surprising that there were no changes in outcomes.An SW-CRT is generally considered a rigorous study design as it includes cluster randomisation.

However, though novel and increasingly popular, this approach is complex and may sometimes add confusion rather than clarity.52–57 Its major appeal is that all clusters will at some point, in a random and sequential fashion, transition from control to intervention condition. For an intervention that is perceived by participants as having more potential for good than harm, this may enhance cluster recruitment. It may also make it possible to conduct a randomised study in scenarios where pragmatic considerations, such as the inability to conduct interventions simultaneously across numerous clusters, may make a parallel randomised study (or any study) infeasible.However, as acknowledged even by its proponents, the added practical and statistical complexity of SW-CRTs often makes them more challenging to properly implement, and compared with traditional parallel cluster randomised trials they may be more prone to biases.53–57 A Consolidated Standards of Reporting Trials extension has been specifically developed in response to these concerns.55 Unique design and analytical considerations include the number of clusters, sequences and periods. Clusters per sequence. And cluster-period sizes.55 56 Concerns include recruitment and selection biases.

Proper accounting for secular trends in outcomes (ie, because of the sequential rather than simultaneous nature of the SW-CRT design, observations from the intervention condition occur on average at a later calendar time, so that the intervention effect may be confounded by an underlying time trend). Accounting for repeated measures on participants and clusters in sample size calculations and analyses (ie, data are not independent). Possible time-varying treatment effects. And the potential for within-cluster contamination of observations obtained under the control or intervention condition.52–56Regarding contamination, a secular trend may be responsible if, for example, institutional activities focused on improving patient outcomes include a general emphasis on communications. There might also be more direct contamination of the intervention among clusters waiting to be crossed over, as described in the context of the Matching Michigan programme.58 Participating in a trial and awareness of being observed may change the behaviour of participants.

For example, in the handover intervention of Jorro-Barón and colleagues,1 some providers in a control condition cluster may, because they are aware of the interest in handovers, begin to implement more standardised practices before the formal shift to the intervention condition. This potentially dilutes any subsequent impact of the intervention by virtue of what could be considered either a Hawthorne effect or a local secular trend, in either case leading to generally better handovers in the preintervention period. Some SW-CRTs include a transition period without any observations to allow for sufficient time to implement the intervention,53 59 thereby creating more contrast. Finally, because of sometimes prolonged PICU length of stay and regularly scheduled resident rotations on and off a unit or service, some patients and providers might overlap the transition from control to intervention state and contribute observations to both, while others will be limited to one or the other. This possibility is not clearly defined by the authors of the current study, but seems unlikely to have had a major statistical effect.Do we need more evidence?.

From an implementation science perspective, handovers are a deeply flawed healthcare process with the demonstrated potential to harm patients. A new tool—I-PASS—has been developed which can be easily and economically taught and subsequently applied by virtually any provider, and many resources are available to assist in implementation.45 It has few, if any, unintended negative consequences to patients or providers and has been associated in at least two extensive and well-conducted (although non-randomised) trials with dramatic reductions in medical errors and adverse events. Notably, these were conducted at a time when there was much less emphasis on and awareness of handover systems, including I-PASS. Thus, there was much greater separation between control and intervention states than would be possible today.Returning to the question posed at the beginning of this commentary, is the inability to demonstrate a favourable impact on clinical outcomes in studies other than those of the developers34 35 a reason to question the value of I-PASS?. For the reasons discussed above, I think not.

In his classic 2008 article,60 ‘The Science of Improvement’, Dr Don Berwick recounts the transformational development of sophisticated statistical analyses in healthcare, of which the randomised clinical trial is the paradigm. While in many instances randomised controlled trials have been invaluable in scientifically affirming or rejecting the utility of specific treatments or interventions, their limitations are more obvious in interventions involving complex social and behavioural change. Berwick illustrates this challenge with the example of hospital rapid response teams, whose benefit was challenged by the results of a large cluster randomised trial. His comments regarding that conflict are equally applicable to the current challenge of demonstrating the impact of standardised handovers on clinical outcomes:These critics refused to accept as evidence the large, positive, accumulating experience of many hospitals that were adapting rapid response for their own use, such as children’s hospitals. How can accumulating local reports of effectiveness of improvement interventions, such as rapid response systems, be reconciled with contrary findings from formal trials with their own varying imperfections?.

The reasons for this apparent gap between science and experience lie deep in epistemology. The introduction of rapid response systems in hospitals is a complex, multicomponent intervention—essentially a process of social change. The effectiveness of these systems is sensitive to an array of influences. Leadership, changing environments, details of implementation, organizational history, and much more. In such complex terrain, the RCT is an impoverished way to learn.

Critics who use it as a truth standard in this context are incorrect.Having personally observed the value of I-PASS, as well as the devastating consequences of inadequate handovers, I vote with Dr Berwick. The evidence for effectiveness is overwhelming and the need for action is urgent—all that is lacking is the will to implement.Ethics statementsPatient consent for publicationNot required.Palliative care is associated with improved patient-centred and caregiver-centred outcomes, higher-quality end-of-life care, and decreased healthcare use among patients with serious illness.1–3 The Centre to Advance Palliative Care has established a set of recommended clinical criteria (or ‘triggers’), including a projected survival of less than 1 year,4 to help clinicians identify patients likely to benefit from palliative care. Nevertheless, referrals often occur within the last 3 months of life5 due in part to clinician overestimation of prognosis.6 A growing number of automated predictive models leverage vast data in the electronic medical record (EMR) to accurately predict short-term mortality risk in real time and can be paired with systems to prompt clinicians to refer to palliative care.7–12 These models hold great promise to overcome the many clinician-level and system-level barriers to improving access to timely palliative care. First, mortality risk prediction algorithms have been shown to outperform clinician prognostic assessment, and clinician–machine collaboration may even outperform both.13 Second, algorithm-based ‘nudges’ that systematically provide prognostic information could address many cognitive biases, including status quo bias and optimism bias,14 15 that make clinicians less apt to identify patients who may benefit from palliative care. Indeed, such models have been shown to improve the frequency of palliative care delivery and patient outcomes in the hospital and clinic settings.9 16 17 With that said, successful implementation of automated prognostic models into routine clinical care at scale requires clinician and patient engagement and support.In this issue of BMJ Quality &.

Safety, Saunders and colleagues report on the acceptability of using the EMR-based Modified Hospitalised-Patient One-Year Mortality Risk (mHOMR) score to alert clinicians to individual patients with a >21% risk of dying within 12 months. The goal of the clinician notification of an elevated risk score was to prompt clinicians to consider palliative care referral.18 In a previously reported feasibility study among 400 hospitalised patients, use of the mHOMR alert was associated with increased rates of goals of care discussions and palliative care consultation in comparison to the preimplementation baseline (34% vs 18%, respectively).19 In the present study, the authors conducted qualitative interviews pre-mHOMR and post-mHOMR implementation among 64 stakeholders, including patients identified at high risk by the mHOMR algorithm, their caregivers, staff and physicians. Thirty-five (55%) participants agreed that the mHOMR tool was acceptable. 14 (22%) were unsure or did not agree. And 15 (23%) did not respond.

Participants identified many potential benefits of the programme, citing the advantages of an automated approach to facilitate and justify clinical decision making. Participants also acknowledged possible barriers, particularly ‘situational challenges’ such as the content, timing and mechanism of provider notification. Additional logistical concerns included alert fatigue, potential redundancy, uncertainty regarding next steps and a worry that certain therapeutic options could be withheld from flagged patients. The authors concluded that clinicians and patients found the automated prognostic trigger to be an acceptable addition to usual clinical care.Saunders et al’s work adds to our understanding of critical perceptions regarding end users’ acceptability of automated prognostic triggers in routine clinical care. The findings from this study align with prior evidence suggesting that clinicians recognise the value of automated, algorithm-based approaches to improve serious illness care.

For example, in a qualitative study of clinicians by Hallen et al, prognostic models confirmed clinicians’ gestalt and served as a tool to help communicate prognosis to patients.20 Clinicians described prognostic models as a tool to facilitate interclinician disagreements, mitigate medicolegal risk, and overcome the tendency to ignore or overestimate prognosis.20 Clinicians also reported that EMR-generated lists of high-risk patients improved their ability to identify potential palliative care beneficiaries in a mixed-methods study by Mason et al.21 In a single-centre pilot study, we similarly found that most clinicians believed that using an EMR-based prognostic model to encourage inpatient palliative care consultation was acceptable.9 However, in the Saunders et al study, as in prior similar work, clinicians highlighted the importance of delivering notifications without causing excess provider workload, redundancy or alert fatigue.16 18 21 Clinicians also raised concerns regarding the accuracy of the prognostic information and the potential for negative effects on patients due to common misperceptions about palliative care being equivalent to hospice.18 20 21 Ultimately, Saunders et al’s work complements and builds on existing literature, demonstrating a general perception that integration of automated prognostic models into routine clinical care could be beneficial and acceptable.Important gaps remain in this literature which were not addressed by the Saunders et al study. For example, there is a need to capture more diverse clinician and patient perspectives, and there was no information provided about the sociodemographic or clinical characteristics of the study participants. Additionally, important themes found in prior studies were not identified in this study. For example, two prior studies of clinicians’ perspectives on automated prognostic triggers for palliative care revealed concerns that prognosis alone may not be a sufficient surrogate indicator of actual palliative care need, or may inadvertently engender clinician overconfidence in an individual patient’s prognosis.9 21 The brevity of the interviews in Saunders et al’s study (mean. 12 min) could suggest all relevant themes may not have emerged in the data analysis.

Additionally, while the inclusion of patient and caregiver perceptions is an important addition, limited information is provided about their perspectives and whether certain themes differed among the stakeholders. In the study from Mason et al, themes unique to patients and caregivers were identified, such as hesitancy due to a lack of understanding of palliative care, a preference to ‘focus on the present’, and a worry that a clinician would not have the time to adequately address advanced care planning or palliative care during their visit.21 Healthcare systems should therefore be prepared to consider their unique workflows, patients and staff prior to implementing one of these programmes.Achieving stakeholder acceptability prior to widespread implementation is essential. An intervention should ideally undergo multiple cycles of optimisation with ongoing appraisal of patient and clinician perspectives prior to wide-scale implementation.22 23 Additionally, it is unclear whether clinicians’ acceptability of the intervention in one setting will generalise to other inpatient health settings. For instance, Saunders et al found that some providers were leery about the use of mHOMR due the need to balance the patient’s acute needs that brought them to the hospital with their long-term priorities that may be better served in the outpatient setting.18 Clinical workflows, patient acuity and patient–provider relationships are markedly different between the inpatient and outpatient settings, suggesting Saunders et al’s findings cannot be extrapolated to outpatient care. This is particularly relevant as many ‘off-the-shelf’ prognostic algorithms are now commercially available that, while accurate, may not be as familiar or acceptable to clinicians as a homegrown model.

Therefore, while Saunders et al’s work is a great addition to the field, additional assessments are needed across different healthcare environments and varying clinical and demographic cohorts to demonstrate that this approach is acceptable in other health settings. It is likely that multiple implementation strategies will be needed to successfully adapt automated prognostic models across a range of clinical settings.Thoughtful consideration of the many forces that alter clinical decision making will also be critical for downstream success of these interventions. Suboptimal clinical decision making is often a result of systemic biases, such as status quo and optimism bias, which result in clinician resistance to change current practice and a belief that their patients are less prone to negative outcomes.14 15 Intentional application of targeted behavioural economics principles will help ensure that the use of prognostic triggers to improve palliative care effectively changes clinical behaviour.24 For example, using an ‘opt-out’ approach for palliative care referral may make the optimal choice the path of least resistance, increasing uptake among clinicians.16 These approaches will need to be balanced against rising clinician alert fatigue25 and resource constraints.Given the implementation challenges that accompany an intervention using prognostic triggers, hybrid effectiveness trials that test both clinical effectiveness and implementation outcomes offer one strategy to advance the integration of automated prognostic models.26 Implementation outcomes are typically based on a framework which provides a systematic way to develop, manage and evaluate interventions. For example, Reach Effectiveness Adoption Implementation Maintenance (RE-AIM) is a framework that measures the impact of a programme based on five factors. Reach, effectiveness, adoption, implementation and maintenance.27 Due to their pragmatic approach, hybrid trials frequently include heterogenous samples and clinical settings that optimise external validity and generalisability.26 28 They can be designed to primarily test the effects of a clinical interventions while observing and gathering information on implementation outcomes (type I), for equal evaluation of both the clinical intervention and implementation strategies (type II), or to primarily assess implementation outcomes while collecting effectiveness data (type III).26 29 For example, Beidas et al used a type I hybrid effectiveness–implementation trial design to test the effectiveness of an exercise intervention for breast cancer.

This study not only evaluated the effectiveness of the intervention but also identified multiple significant implementation barriers such as cost, referral logistics and patient selection challenges which informed their subsequent dissemination efforts.30 Prospective, randomised, hybrid effectiveness–implementation designs focusing on other key implementation outcomes are a logical and necessary next step in advancing the field. In total, the work by Saunders et al demonstrates the potential acceptability of an automated prognostic model to improve the timeliness of palliative care, setting the stage for further work to optimise and implement these programmes into real-world clinical care.Ethics statementsPatient consent for publicationNot required..

In this issue of BMJ Quality and Safety, Jorro-Barón and colleagues1 report the findings of a stepped-wedge cluster randomised trial (SW-CRT) to evaluate the implementation of the I-PASS handover system among six paediatric intensive care units (PICUs) at five Argentinian hospitals between July 2018 and kamagra online uk May 2019. According to the authors, prior to the intervention there were complaints that handovers kamagra online uk were ‘…lengthy, disorganized, …participants experienced problems with interruptions, distractions, and … senior professionals had problems accepting dissent’.Adverse events were assessed by two independent reviewers using the Global Assessment of Pediatric Patient Safety instrument. Study results demonstrated significantly improved handover compliance in the intervention group, validating Kirkpatrick Level 3 (behavioural change)2 effectiveness of the training initiative.

Notably, however, on the primary outcome there were no differences between control and intervention groups regarding preventable adverse events per 1000 kamagra online uk days of hospitalisation (control 60.4 (37.5–97.4) vs intervention 60.4 (33.2–109.9), p=0.998, risk ratio. 1.0 (0.74–1.34)). Regarding balancing measures, there was kamagra online uk no observed difference in the ‘full-shift’ handover duration (control 35.7 min (29.6–41.8).

Intervention 34.7 min (26.5–42.1), p=0.490), although more time was spent on individual patient handovers in the intervention period (7.29 min (5.77–8.81). Control 5.96 kamagra online uk min (4.69–7.23). P=0.001).

From the provider perspective, preintervention and postintervention Agency for Healthcare Research and Quality (AHRQ) safety culture surveys did not show significant differences in their responses to communication-focused questions before and after the intervention.Thus, consistent with all previous studies, I-PASS was implemented successfully and handover quality improved. However, is the lack of association of I-PASS implementation with clinical outcomes and adverse events in this study a concern?. To answer this question, it is necessary to review the origins of I-PASS more than a decade ago and its continually expanding evidence base.Healthcare has a handover problemHandovers are among the most vulnerable reoccurring processes in healthcare.

In the AHRQ safety culture survey,3 the handovers and transitions of care domain is consistently among the lowest scoring, and handover and communication issues are among the most common cause of Joint Commission Sentinel Events and the subject of Joint Commission Sentinel Event Alert Issue 58.4 A study by CRICO Strategies found that communication issues were a factor in 30% of 23 658 malpractice claims filed from 2009 to 2013, accounting for $1.7 billion in incurred losses.5 The importance of handovers and care transitions for trainees is specifically discussed in a Clinical Learning Environment Review Issue Brief published by the Accreditation Council for Graduate Medical Education (ACGME),6 and Section VI.E.3 (Transitions of Care) of the ACGME Common Program Requirements (Residency) addresses the requirement for residents to be taught and to use structured handovers.7Both the numbers of handovers and handover-related problems have increased in contemporary practice because of greater patient complexity and the expanding number and types of providers involved in a typical patient’s care. Further, in teaching institutions, resident work-hour restrictions have resulted in the need for complex coverage schemes. Off-hours care is often provided by ‘cross-covering’, ‘float’ or ‘moonlighting’ practitioners who are responsible for numerous unfamiliar patients during their shifts, thus imposing an even greater need for effective handovers.

The net effect of all these changes may be inconsistent, fragmented care resulting from suboptimal handovers from one provider, service or hospital to another, with resulting medical errors (often of omission) and adverse events.Structured, standardised handoversThese serious vulnerabilities have led to pleas for more consistent, structured and standardised handovers.8–11 In addition to their use in routine shift-to-shift provider sign-off, these may be of particular value in the high-risk transfers of critically ill patients, such as from operating rooms to postoperative care units and ICUs12–16. Admissions to a surgery unit17. Management of trauma patients18–20.

ICU to general ward transfers21 22. Night and weekend coverage of large services, many of whose patients are unfamiliar to the physician receiving the handover23–28. And end-of-rotation resident transitions.29–31Given these considerations, standardised handovers, often involving mnemonic devices, have been widely advocated and studied in the past several decades, though many lack rigorous evaluation and few if any showed demonstrable associations with outcomes.32 33 Further, although some individual hospitals, units and services have implemented their own idiosyncratic handover systems, this does not solve the issue of handover inconsistency between different care delivery sites.

A basic, common framework that could be customised to individual use cases would clearly be preferable.The I-PASS systemResponding to these concerns, the I-PASS Study Group was initiated in 2009 and the I-PASS Institute in 2016. Although numerous other systems are available, since its pilot studies a decade ago,34 35 I-PASS has emerged as the dominant system in healthcare for structured, standardised handovers. This system is specifically designed for healthcare applications.

It is based on adult educational principles and simple to use. It has been extensively validated in the peer-reviewed literature encompassing studies at multiple institutions in the USA and internationally34–40. And extensive training materials are available to assist programmes in implementation.39 41–45 Ideally, this system is implemented hospital-wide, which addresses the issue of cross-unit and cross-service transfers.I-PASS includes five major elements regarded as important for every handover—illness severity, patient summary, action list, situation awareness/contingency planning and synthesis by receiver.

The first three of these elements are often included in non-structured handovers, although not necessarily in a specific sequence or format. The last two I-PASS elements—situational awareness/contingency planning and synthesis—have not historically been included in typical handover practice. The former assures that any anticipated problems are conveyed from the handover giver to the incoming provider and that appropriate responses to these issues are discussed.

Synthesis is closed-loop communication, with brief read-back of the handover information by the receiver to assure their accurate comprehension, followed by an opportunity for questions and discussion. This read-back of mission-critical communications is standard operating practice in other high-reliability settings such as aviation, the military and nuclear power. It is essential to establishing a shared mental model of the current state and any potential concerns.

However, other than in I-PASS, it is quite uncommon in healthcare, with the potential exception of confirming verbal or telephonic orders.I-PASS validationIn an initial study of I-PASS handover implementation by residents on two general inpatient paediatric units at Boston Children’s Hospital,34 written handovers were more comprehensive and had fewer omissions of key data, and mean time spent on verbal handover sessions did not change significantly (32.3 min vs 33.2 min). Medical errors and adverse events were ascertained prospectively by research nurse reviewers and independent physician investigators. Following I-PASS implementation, preventable adverse events decreased from 3.3 (95% CI 1.7 to 4.8) to 1.5 (95% CI 0.51 to 2.4) per 100 admissions (p=0.04), and medical error rates decreased significantly from 33.8 per 100 admissions (95% CI 27.3 to 40.3) to 18.3 per 100 admissions (95% CI 14.7 to 21.9.

P<0.001). A commentary by Horwitz46 noted that this was ‘…by far the most comprehensive study of the direct effects of handoff interventions on outcomes within the context of existing work-hour regulations and is the first to demonstrate an associated significant decrease in medical errors on a large scale’, while also noting limitations including its uncontrolled, ‘before and after’ design, confounding by secular changes, Hawthorne effects and inability to blind the nurses collecting adverse event data.The more expansive, landmark I-PASS study was conducted by Starmer and colleagues37 among nine paediatric hospitals and 10 740 patient admissions between January 2011 and May 2013. Handover quality was evaluated, and medical errors and adverse events were ascertained by active surveillance, including on-site nurse review of medical records, orders, formal incident reports, nursing reports and daily medical error reports from residents.

Independent physician investigators classified occurrences as adverse events, near misses or exclusions, and they subclassified adverse events as preventable or non-preventable. Results revealed a 23% reduction in medical errors from the preintervention to the postintervention period (24.5 vs 18.8 per 100 admissions, p<0.001) and a 30% reduction in preventable adverse events (4.7 vs 3.3 events per 100 admissions, p<0.001). Inclusion of prespecified elements in written and verbal handovers increased significantly, and there was no significant change in handover time per patient (2.4 vs 2.5 min.

P=0.55).Subsequent investigations in other institutions have replicated many of the findings of the original I-PASS studies, with higher postintervention inclusion rates of critical handover elements. Fewer mistakes or omissions. Greater provider satisfaction with handover organisation and information conveyed.

Unchanged or shorter handoff times. And decreased handover interruptions (probably reflecting greater attention to the importance of the handover process).36 40 47–50 In a mentored implementation study conducted in 2015–2016 among 16 hospitals (five community hospitals, 11 academic centres and multiple specialties), handover quality improved, and there was a provider-reported 27% reduction in adverse events.38 Among nurses at Boston Children’s Hospital, I-PASS implementation was associated with significant decreases in handover-related care failures.40In recognition of its achievements in improving healthcare quality, the I-PASS Study Group was awarded the 2016 John M Eisenberg Award for Patient Safety and Quality by the National Quality Forum and the Joint Commission.The challenge of linking handovers to clinical outcomes and eventsAlthough investigations from many centres, including the report of Jorro-Barrón and colleagues,1 have now confirmed that I-PASS can be readily assimilated and used by clinicians, most of these have either not rigorously assessed adverse events, medical errors and other clinical outcomes (Kirkpatrick Level 4 evaluation) or have failed to demonstrate significant postintervention improvements in these clinical outcomes. Why is this, and should current or potential I-PASS users be concerned?.

With regard to the first question, there are practical considerations that complicate the rigorous study of clinical outcome improvements associated with I-PASS (or any other handover system). Notwithstanding the importance of effective communications, these are only one of many provider processes and hospital systems, not to mention the overall hospital quality and safety culture, that impact a patient’s clinical outcome. In most hospitals, a diverse portfolio of quality and safety improvement initiatives are always being conducted.

Disentangling and isolating the effects of any one specific intervention, such as I-PASS handovers, is challenging if not impossible. At a minimum, it requires real-time, prospective monitoring by trained nurse or physician reviewers as in the original I-PASS studies, a research design which realistically is unlikely to be reproduced. Ideally, the study design would also include blinding of the study period (control or intervention) and blinding of observers, the former of which is virtually impossible for this type of intervention.Further, if other provider processes and hospital systems are functioning at a high level, they may partially offset the impact of suboptimal communications and make it even more challenging to demonstrate significant improvements.

The current study of Jorro-Barón and colleagues,1 which uses PICUs as the unit of analysis, illustrates this concept. PICUs are typically among the most compulsive, detail-oriented units in any hospital, even if they may have nominally ‘non-standardized’ handovers.Study design. The SW-CRTIn an attempt to address the limitations of some previous studies, Parent and colleagues51 studied eight medical and surgical ICUs across two academic tertiary teaching hospitals using an SW-CRT design.

Clinician self-assessment of having been inadequately prepared for their shift because of a poor-quality handoff decreased from 35 of 343 handoffs (10.2%) in the control arm to 53 of 740 handoffs (7.2%) postintervention (OR 0.19. 95% CI 0.03 to 0.74. P=0.03).

€˜Last-minute’, early morning order writing decreased, and handover duration increased but not significantly (+5.5 min. 95% CI 0.34 to 9.39. P=0.30).

As in the current study of Jorro-Barón and colleagues,1 who also employed an SW-CRT, there were no associated changes in clinical outcomes such as ICU length of stay, duration of mechanical ventilation or necessity for reintubation. The authors comment that given high baseline quality of care in these ICUs, it was not surprising that there were no changes in outcomes.An SW-CRT is generally considered a rigorous study design as it includes cluster randomisation. However, though novel and increasingly popular, this approach is complex and may sometimes add confusion rather than clarity.52–57 Its major appeal is that all clusters will at some point, in a random and sequential fashion, transition from control to intervention condition.

For an intervention that is perceived by participants as having more potential for good than harm, this may enhance cluster recruitment. It may also make it possible to conduct a randomised study in scenarios where pragmatic considerations, such as the inability to conduct interventions simultaneously across numerous clusters, may make a parallel randomised study (or any study) infeasible.However, as acknowledged even by its proponents, the added practical and statistical complexity of SW-CRTs often makes them more challenging to properly implement, and compared with traditional parallel cluster randomised trials they may be more prone to biases.53–57 A Consolidated Standards of Reporting Trials extension has been specifically developed in response to these concerns.55 Unique design and analytical considerations include the number of clusters, sequences and periods. Clusters per sequence.

And cluster-period sizes.55 56 Concerns include recruitment and selection biases. Proper accounting for secular trends in outcomes (ie, because of the sequential rather than simultaneous nature of the SW-CRT design, observations from the intervention condition occur on average at a later calendar time, so that the intervention effect may be confounded by an underlying time trend). Accounting for repeated measures on participants and clusters in sample size calculations and analyses (ie, data are not independent).

Possible time-varying treatment effects. And the potential for within-cluster contamination of observations obtained under the control or intervention condition.52–56Regarding contamination, a secular trend may be responsible if, for example, institutional activities focused on improving patient outcomes include a general emphasis on communications. There might also be more direct contamination of the intervention among clusters waiting to be crossed over, as described in the context of the Matching Michigan programme.58 Participating in a trial and awareness of being observed may change the behaviour of participants.

For example, in the handover intervention of Jorro-Barón and colleagues,1 some providers in a control condition cluster may, because they are aware of the interest in handovers, begin to implement more standardised practices before the formal shift to the intervention condition. This potentially dilutes any subsequent impact of the intervention by virtue of what could be considered either a Hawthorne effect or a local secular trend, in either case leading to generally better handovers in the preintervention period. Some SW-CRTs include a transition period without any observations to allow for sufficient time to implement the intervention,53 59 thereby creating more contrast.

Finally, because of sometimes prolonged PICU length of stay and regularly scheduled resident rotations on and off a unit or service, some patients and providers might overlap the transition from control to intervention state and contribute observations to both, while others will be limited to one or the other. This possibility is not clearly defined by the authors of the current study, but seems unlikely to have had a major statistical effect.Do we need more evidence?. From an implementation science perspective, handovers are a deeply flawed healthcare process with the demonstrated potential to harm patients.

A new tool—I-PASS—has been developed which can be easily and economically taught and subsequently applied by virtually any provider, and many resources are available to assist in implementation.45 It has few, if any, unintended negative consequences to patients or providers and has been associated in at least two extensive and well-conducted (although non-randomised) trials with dramatic reductions in medical errors and adverse events. Notably, these were conducted at a time when there was much less emphasis on and awareness of handover systems, including I-PASS. Thus, there was much greater separation between control and intervention states than would be possible today.Returning to the question posed at the beginning of this commentary, is the inability to demonstrate a favourable impact on clinical outcomes in studies other than those of the developers34 35 a reason to question the value of I-PASS?.

For the reasons discussed above, I think not. In his classic 2008 article,60 ‘The Science of Improvement’, Dr Don Berwick recounts the transformational development of sophisticated statistical analyses in healthcare, of which the randomised clinical trial is the paradigm. While in many instances randomised controlled trials have been invaluable in scientifically affirming or rejecting the utility of specific treatments or interventions, their limitations are more obvious in interventions involving complex social and behavioural change.

Berwick illustrates this challenge with the example of hospital rapid response teams, whose benefit was challenged by the results of a large cluster randomised trial. His comments regarding that conflict are equally applicable to the current challenge of demonstrating the impact of standardised handovers on clinical outcomes:These critics refused to accept as evidence the large, positive, accumulating experience of many hospitals that were adapting rapid response for their own use, such as children’s hospitals. How can accumulating local reports of effectiveness of improvement interventions, such as rapid response systems, be reconciled with contrary findings from formal trials with their own varying imperfections?.

The reasons for this apparent gap between science and experience lie deep in epistemology. The introduction of rapid response systems in hospitals is a complex, multicomponent intervention—essentially a process of social change. The effectiveness of these systems is sensitive to an array of influences.

Leadership, changing environments, details of implementation, organizational history, and much more. In such complex terrain, the RCT is an impoverished way to learn. Critics who use it as a truth standard in this context are incorrect.Having personally observed the value of I-PASS, as well as the devastating consequences of inadequate handovers, I vote with Dr Berwick.

The evidence for effectiveness is overwhelming and the need for action is urgent—all that is lacking is the will to implement.Ethics statementsPatient consent for publicationNot required.Palliative care is associated with improved patient-centred and caregiver-centred outcomes, higher-quality end-of-life care, and decreased healthcare use among patients with serious illness.1–3 The Centre to Advance Palliative Care has established a set of recommended clinical criteria (or ‘triggers’), including a projected survival of less than 1 year,4 to help clinicians identify patients likely to benefit from palliative care. Nevertheless, referrals often occur within the last 3 months of life5 due in part to clinician overestimation of prognosis.6 A growing number of automated predictive models leverage vast data in the electronic medical record (EMR) to accurately predict short-term mortality risk in real time and can be paired with systems to prompt clinicians to refer to palliative care.7–12 These models hold great promise to overcome the many clinician-level and system-level barriers to improving access to timely palliative care. First, mortality risk prediction algorithms have been shown to outperform clinician prognostic assessment, and clinician–machine collaboration may even outperform both.13 Second, algorithm-based ‘nudges’ that systematically provide prognostic information could address many cognitive biases, including status quo bias and optimism bias,14 15 that make clinicians less apt to identify patients who may benefit from palliative care.

Indeed, such models have been shown to improve the frequency of palliative care delivery and patient outcomes in the hospital and clinic settings.9 16 17 With that said, successful implementation of automated prognostic models into routine clinical care at scale requires clinician and patient engagement and support.In this issue of BMJ Quality &. Safety, Saunders and colleagues report on the acceptability of using the EMR-based Modified Hospitalised-Patient One-Year Mortality Risk (mHOMR) score to alert clinicians to individual patients with a >21% risk of dying within 12 months. The goal of the clinician notification of an elevated risk score was to prompt clinicians to consider palliative care referral.18 In a previously reported feasibility study among 400 hospitalised patients, use of the mHOMR alert was associated with increased rates of goals of care discussions and palliative care consultation in comparison to the preimplementation baseline (34% vs 18%, respectively).19 In the present study, the authors conducted qualitative interviews pre-mHOMR and post-mHOMR implementation among 64 stakeholders, including patients identified at high risk by the mHOMR algorithm, their caregivers, staff and physicians.

Thirty-five (55%) participants agreed that the mHOMR tool was acceptable. 14 (22%) were unsure or did not agree. And 15 (23%) did not respond.

Participants identified many potential benefits of the programme, citing the advantages of an automated approach to facilitate and justify clinical decision making. Participants also acknowledged possible barriers, particularly ‘situational challenges’ such as the content, timing and mechanism of provider notification. Additional logistical concerns included alert fatigue, potential redundancy, uncertainty regarding next steps and a worry that certain therapeutic options could be withheld from flagged patients.

The authors concluded that clinicians and patients found the automated prognostic trigger to be an acceptable addition to usual clinical care.Saunders et al’s work adds to our understanding of critical perceptions regarding end users’ acceptability of automated prognostic triggers in routine clinical care. The findings from this study align with prior evidence suggesting that clinicians recognise the value of automated, algorithm-based approaches to improve serious illness care. For example, in a qualitative study of clinicians by Hallen et al, prognostic models confirmed clinicians’ gestalt and served as a tool to help communicate prognosis to patients.20 Clinicians described prognostic models as a tool to facilitate interclinician disagreements, mitigate medicolegal risk, and overcome the tendency to ignore or overestimate prognosis.20 Clinicians also reported that EMR-generated lists of high-risk patients improved their ability to identify potential palliative care beneficiaries in a mixed-methods study by Mason et al.21 In a single-centre pilot study, we similarly found that most clinicians believed that using an EMR-based prognostic model to encourage inpatient palliative care consultation was acceptable.9 However, in the Saunders et al study, as in prior similar work, clinicians highlighted the importance of delivering notifications without causing excess provider workload, redundancy or alert fatigue.16 18 21 Clinicians also raised concerns regarding the accuracy of the prognostic information and the potential for negative effects on patients due to common misperceptions about palliative care being equivalent to hospice.18 20 21 Ultimately, Saunders et al’s work complements and builds on existing literature, demonstrating a general perception that integration of automated prognostic models into routine clinical care could be beneficial and acceptable.Important gaps remain in this literature which were not addressed by the Saunders et al study.

For example, there is a need to capture more diverse clinician and patient perspectives, and there was no information provided about the sociodemographic or clinical characteristics of the study participants. Additionally, important themes found in prior studies were not identified in this study. For example, two prior studies of clinicians’ perspectives on automated prognostic triggers for palliative care revealed concerns that prognosis alone may not be a sufficient surrogate indicator of actual palliative care need, or may inadvertently engender clinician overconfidence in an individual patient’s prognosis.9 21 The brevity of the interviews in Saunders et al’s study (mean.

12 min) could suggest all relevant themes may not have emerged in the data analysis. Additionally, while the inclusion of patient and caregiver perceptions is an important addition, limited information is provided about their perspectives and whether certain themes differed among the stakeholders. In the study from Mason et al, themes unique to patients and caregivers were identified, such as hesitancy due to a lack of understanding of palliative care, a preference to ‘focus on the present’, and a worry that a clinician would not have the time to adequately address advanced care planning or palliative care during their visit.21 Healthcare systems should therefore be prepared to consider their unique workflows, patients and staff prior to implementing one of these programmes.Achieving stakeholder acceptability prior to widespread implementation is essential.

An intervention should ideally undergo multiple cycles of optimisation with ongoing appraisal of patient and clinician perspectives prior to wide-scale implementation.22 23 Additionally, it is unclear whether clinicians’ acceptability of the intervention in one setting will generalise to other inpatient health settings. For instance, Saunders et al found that some providers were leery about the use of mHOMR due the need to balance the patient’s acute needs that brought them to the hospital with their long-term priorities that may be better served in the outpatient setting.18 Clinical workflows, patient acuity and patient–provider relationships are markedly different between the inpatient and outpatient settings, suggesting Saunders et al’s findings cannot be extrapolated to outpatient care. This is particularly relevant as many ‘off-the-shelf’ prognostic algorithms are now commercially available that, while accurate, may not be as familiar or acceptable to clinicians as a homegrown model.

Therefore, while Saunders et al’s work is a great addition to the field, additional assessments are needed across different healthcare environments and varying clinical and demographic cohorts to demonstrate that this approach is acceptable in other health settings. It is likely that multiple implementation strategies will be needed to successfully adapt automated prognostic models across a range of clinical settings.Thoughtful consideration of the many forces that alter clinical decision making will also be critical for downstream success of these interventions. Suboptimal clinical decision making is often a result of systemic biases, such as status quo and optimism bias, which result in clinician resistance to change current practice and a belief that their patients are less prone to negative outcomes.14 15 Intentional application of targeted behavioural economics principles will help ensure that the use of prognostic triggers to improve palliative care effectively changes clinical behaviour.24 For example, using an ‘opt-out’ approach for palliative care referral may make the optimal choice the path of least resistance, increasing uptake among clinicians.16 These approaches will need to be balanced against rising clinician alert fatigue25 and resource constraints.Given the implementation challenges that accompany an intervention using prognostic triggers, hybrid effectiveness trials that test both clinical effectiveness and implementation outcomes offer one strategy to advance the integration of automated prognostic models.26 Implementation outcomes are typically based on a framework which provides a systematic way to develop, manage and evaluate interventions.

For example, Reach Effectiveness Adoption Implementation Maintenance (RE-AIM) is a framework that measures the impact of a programme based on five factors. Reach, effectiveness, adoption, implementation and maintenance.27 Due to their pragmatic approach, hybrid trials frequently include heterogenous samples and clinical settings that optimise external validity and generalisability.26 28 They can be designed to primarily test the effects of a clinical interventions while observing and gathering information on implementation outcomes (type I), for equal evaluation of both the clinical intervention and implementation strategies (type II), or to primarily assess implementation outcomes while collecting effectiveness data (type III).26 29 For example, Beidas et al used a type I hybrid effectiveness–implementation trial design to test the effectiveness of an exercise intervention for breast cancer. This study not only evaluated the effectiveness of the intervention but also identified multiple significant implementation barriers such as cost, referral logistics and patient selection challenges which informed their subsequent dissemination efforts.30 Prospective, randomised, hybrid effectiveness–implementation designs focusing on other key implementation outcomes are a logical and necessary next step in advancing the field.

In total, the work by Saunders et al demonstrates the potential acceptability of an automated prognostic model to improve the timeliness of palliative care, setting the stage for further work to optimise and implement these programmes into real-world clinical care.Ethics statementsPatient consent for publicationNot required..

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