From Chaos To Calm: A Life Changed By Ketamine


An anesthetic and sometimes-party drug, ketamine is helping some patients calm the symptoms of mental disorders.

For six years now, life has been really good for James. He has a great job as the creative director of an advertising firm in New York City. He enjoys spending time with his wife and kids.

And it has all been possible, he says, because for the past six years he has been taking a drug called ketamine.

Before ketamine, James was unable to work or focus his thoughts. His mind was filled with violent images. And his mood could go from ebullient to dark in a matter of minutes.

Ketamine “helped me get my life back,” says James, who asked that we not use his last name to protect his career.

Ketamine was developed as a human and animal anesthetic in the 1960s. And almost from the time it reached the market it has also been used as a mind-bending party drug.

But ketamine’s story took a surprising turn in 2006, when researchers at the National Institutes of Health showed that an intravenous dose could relieve severe depression in a matter of hours. Since then, doctors have prescribed ketamine “off label” to thousands of depressed patients who don’t respond to other drugs.

And pharmaceutical companies are testing several new ketamine-related drugs to treat depression. Johnson & Johnson expects to seek approval for its nasal spray esketamine later this year, though the approval would be limited to use in a clinical setting.

Meanwhile, doctors have begun trying ketamine on patients with a wide range of psychiatric disorders other than depression. And there is now growing evidence it can help people with anxiety, bipolar disorder, post-traumatic stress disorder, and perhaps even obsessive-compulsive disorder.

“I think it’s actually one of the biggest advances in psychiatry in a very long time,” says Dr. Martin Teicher, an associate professor of psychiatry at Harvard Medical School and director of the Developmental Biopsychiatry Research Program at McLean Hospital.

Ketamine may also offer new hope for people like James who have symptoms of several different psychiatric disorders.

James had a happy childhood, he says. But his thoughts were out of control. “I always felt like I was crossing a freeway and my thoughts were just racing past me,” he says.

He spent much of his childhood terrified of “an unknown, an ambiguous force out there.” The fear was “overwhelming,” he says. “I literally slept with the cover over my head with just room to breathe through my mouth until I went to college.”

And there was something else about James: his body temperature.

“I overheated constantly,” he says. “I would wear shorts all year long. In my 20s in my apartment I would sleep with the windows open in the middle of the winter.”

In his late 20s, James saw a doctor who told him he had attention deficit hyperactivity disorder. So he started taking stimulants.

At first, the pills helped him focus. Then they didn’t, no matter how many he took.

He’d done well as an idea guy in the advertising industry. But now James was trying to work at home, and it wasn’t going well.

“ADHD pills will make you interested in anything,” he says. “So I was putting the desk together and taking the desk apart. I was putting a laptop stand together and taking it apart. I was going in a massive downward spiral.”

James had always suffered from mood swings. But now they were rapid and extreme. And he couldn’t stop thinking about gruesome scenarios, like a murderer coming for his family.

“My wife took a summer off to be with me because she was scared of what was going to happen to me,” he says. “She would go to work for a few hours, then rush home. There would be times I’d call her just screaming, ‘Please come home. I can’t get through another minute.’ ”

Eventually, James found his way to Dr. Demitri Papolos, an associate professor of clinical psychiatry at Albert Einstein College of Medicine.

“He was like a whirling dervish when he came into my office,” Papolos says. “He was extremely fearful and scanning the environment all the time and he overheated at the drop of a hat.”

Papolos diagnosed James with a variant of bipolar disorder he calls the “fear of harm phenotype.” It typically appears in childhood and often doesn’t respond to traditional psychiatric drugs.

But Papolos has found that the condition does respond to ketamine. “It’s been transformational,” he says.

In January, Papolos published a study of 45 children with the problem. They inhaled a nasal mist containing ketamine about twice a week. Nearly all got dramatically better.

Scientists still aren’t sure why ketamine works, but there’s evidence that it encourages the brain to rewire, to alter the connections between cells. That process has been linked to recovery from depression. And it may also explain why ketamine helps people who have symptoms associated with several different psychiatric disorders.

“I think it’s having multiple effects, and that means it’s probably useful for multiple different disorders,” Teicher says.

One of those effects involves a part of the brain involved in temperature regulation. And that could explain why patients like James usually stop overheating once they are taking ketamine.

James started taking a ketamine nasal spray every other day. He says his response was dramatic.

“One day I turn to my wife and I’m like, ‘I feel calm today. I don’t know if it’s the sun coming in, I don’t know if it’s just the way we’re sitting here, but I feel like I could go and sit at the computer and work.’ ”

The next day, James did sit down at his computer. A month later, he was back at work.

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Now, you can hold a copy of your brain in the palm of your hand


New 3D printing technique enables faster, better, and cheaper models of patient-specific medical data for research and diagnosis

Summary:
Medical imaging technologies like MRI and CT scans produce high-resolution images as a series of ‘slices,’ making them an obvious complement to 3D printers, which also print in slices. However, the process of manually ‘thresholding’ medical scans to define objects to be printed is prohibitively expensive and time-consuming. A new method converts medical data into dithered bitmaps, allowing custom 3D-printed models of patient data to be printed in a fraction of the time.

This 3D-printed model of Steven Keating’s skull and brain clearly shows his brain tumor and other fine details thanks to the new data processing method pioneered by the study’s authors.
Credit: Wyss Institute at Harvard University

What if you could hold a physical model of your own brain in your hands, accurate down to its every unique fold? That’s just a normal part of life for Steven Keating, Ph.D., who had a baseball-sized tumor removed from his brain at age 26 while he was a graduate student in the MIT Media Lab’s Mediated Matter group. Curious to see what his brain actually looked like before the tumor was removed, and with the goal of better understanding his diagnosis and treatment options, Keating collected his medical data and began 3D printing his MRI and CT scans, but was frustrated that existing methods were prohibitively time-intensive, cumbersome, and failed to accurately reveal important features of interest. Keating reached out to some of his group’s collaborators, including members of the Wyss Institute at Harvard University, who were exploring a new method for 3D printing biological samples.

“It never occurred to us to use this approach for human anatomy until Steve came to us and said, ‘Guys, here’s my data, what can we do?” says Ahmed Hosny, who was a Research Fellow with at the Wyss Institute at the time and is now a machine learning engineer at the Dana-Farber Cancer Institute. The result of that impromptu collaboration — which grew to involve James Weaver, Ph.D., Senior Research Scientist at the Wyss Institute; Neri Oxman, Ph.D., Director of the MIT Media Lab’s Mediated Matter group and Associate Professor of Media Arts and Sciences; and a team of researchers and physicians at several other academic and medical centers in the US and Germany — is a new technique that allows images from MRI, CT, and other medical scans to be easily and quickly converted into physical models with unprecedented detail. The research is reported in 3D Printing and Additive Manufacturing.

“I nearly jumped out of my chair when I saw what this technology is able to do,” says Beth Ripley, M.D. Ph.D., an Assistant Professor of Radiology at the University of Washington and clinical radiologist at the Seattle VA, and co-author of the paper. “It creates exquisitely detailed 3D-printed medical models with a fraction of the manual labor currently required, making 3D printing more accessible to the medical field as a tool for research and diagnosis.”

Imaging technologies like MRI and CT scans produce high-resolution images as a series of “slices” that reveal the details of structures inside the human body, making them an invaluable resource for evaluating and diagnosing medical conditions. Most 3D printers build physical models in a layer-by-layer process, so feeding them layers of medical images to create a solid structure is an obvious synergy between the two technologies.

However, there is a problem: MRI and CT scans produce images with so much detail that the object(s) of interest need to be isolated from surrounding tissue and converted into surface meshes in order to be printed. This is achieved via either a very time-intensive process called “segmentation” where a radiologist manually traces the desired object on every single image slice (sometimes hundreds of images for a single sample), or an automatic “thresholding” process in which a computer program quickly converts areas that contain grayscale pixels into either solid black or solid white pixels, based on a shade of gray that is chosen to be the threshold between black and white. However, medical imaging data sets often contain objects that are irregularly shaped and lack clear, well-defined borders; as a result, auto-thresholding (or even manual segmentation) often over- or under-exaggerates the size of a feature of interest and washes out critical detail.

The new method described by the paper’s authors gives medical professionals the best of both worlds, offering a fast and highly accurate method for converting complex images into a format that can be easily 3D printed. The key lies in printing with dithered bitmaps, a digital file format in which each pixel of a grayscale image is converted into a series of black and white pixels, and the density of the black pixels is what defines the different shades of gray rather than the pixels themselves varying in color.

Similar to the way images in black-and-white newsprint use varying sizes of black ink dots to convey shading, the more black pixels that are present in a given area, the darker it appears. By simplifying all pixels from various shades of gray into a mixture of black or white pixels, dithered bitmaps allow a 3D printer to print complex medical images using two different materials that preserve all the subtle variations of the original data with much greater accuracy and speed.

The team of researchers used bitmap-based 3D printing to create models of Keating’s brain and tumor that faithfully preserved all of the gradations of detail present in the raw MRI data down to a resolution that is on par with what the human eye can distinguish from about 9-10 inches away. Using this same approach, they were also able to print a variable stiffness model of a human heart valve using different materials for the valve tissue versus the mineral plaques that had formed within the valve, resulting in a model that exhibited mechanical property gradients and provided new insights into the actual effects of the plaques on valve function.

“Our approach not only allows for high levels of detail to be preserved and printed into medical models, but it also saves a tremendous amount of time and money,” says Weaver, who is the corresponding author of the paper. “Manually segmenting a CT scan of a healthy human foot, with all its internal bone structure, bone marrow, tendons, muscles, soft tissue, and skin, for example, can take more than 30 hours, even by a trained professional — we were able to do it in less than an hour.”

The researchers hope that their method will help make 3D printing a more viable tool for routine exams and diagnoses, patient education, and understanding the human body. “Right now, it’s just too expensive for hospitals to employ a team of specialists to go in and hand-segment image data sets for 3D printing, except in extremely high-risk or high-profile cases. We’re hoping to change that,” says Hosny.

In order for that to happen, some entrenched elements of the medical field need to change as well. Most patients’ data are compressed to save space on hospital servers, so it’s often difficult to get the raw MRI or CT scan files needed for high-resolution 3D printing. Additionally, the team’s research was facilitated through a joint collaboration with leading 3D printer manufacturer Stratasys, which allowed access to their 3D printer’s intrinsic bitmap printing capabilities. New software packages also still need to be developed to better leverage these capabilities and make them more accessible to medical professionals.

Despite these hurdles, the researchers are confident that their achievements present a significant value to the medical community. “I imagine that sometime within the next 5 years, the day could come when any patient that goes into a doctor’s office for a routine or non-routine CT or MRI scan will be able to get a 3D-printed model of their patient-specific data within a few days,” says Weaver.

Keating, who has become a passionate advocate of efforts to enable patients to access their own medical data, still 3D prints his MRI scans to see how his skull is healing post-surgery and check on his brain to make sure his tumor isn’t coming back. “The ability to understand what’s happening inside of you, to actually hold it in your hands and see the effects of treatment, is incredibly empowering,” he says.

“Curiosity is one of the biggest drivers of innovation and change for the greater good, especially when it involves exploring questions across disciplines and institutions. The Wyss Institute is proud to be a space where this kind of cross-field innovation can flourish,” says Wyss Institute Founding Director Donald Ingber, M.D., Ph.D., who is also the Judah Folkman Professor of Vascular Biology at Harvard Medical School (HMS) and the Vascular Biology Program at Boston Children’s Hospital, as well as Professor of Bioengineering at Harvard’s John A. Paulson School of Engineering and Applied Sciences (SEAS).

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Pediatric Medication Safety in the Emergency Department


Abstract

Pediatric patients cared for in emergency departments (EDs) are at high risk of medication errors for a variety of reasons. A multidisciplinary panel was convened by the Emergency Medical Services for Children program and the American Academy of Pediatrics Committee on Pediatric Emergency Medicine to initiate a discussion on medication safety in the ED. Top opportunities identified to improve medication safety include using kilogram-only weight-based dosing, optimizing computerized physician order entry by using clinical decision support, developing a standard formulary for pediatric patients while limiting variability of medication concentrations, using pharmacist support within EDs, enhancing training of medical professionals, systematizing the dispensing and administration of medications within the ED, and addressing challenges for home medication administration before discharge.

 

  • Abbreviations:
    AAP
    American Academy of Pediatrics
    ACEP
    American College of Emergency Physicians
    ADE
    adverse drug event
    CDS
    clinical decision support
    CPOE
    computerized physician order entry
    ED
    emergency department
    ENA
    Emergency Nurses Association

 

Background

Despite a national focus on patient safety since the publication of the Institute of Medicine (now the National Academy of Medicine) report “To Err is Human” in 1999, medical errors remain a leading cause of morbidity and mortality across the United States.1 Medication errors are by far the most common type of medical error occurring in hospitalized patients,2 and the medication error rate in pediatric patients has been found to be as much as 3 times the rate in adult patients.3,4 Because many medication errors and adverse drug events (ADEs) are preventable,1 strategies to improve medication safety are an essential component of an overall approach to providing quality care to children.

The pediatric emergency care setting is recognized as a high-risk environment for medication errors because of a number of factors, including medically complex patients with multiple medications who are unknown to emergency department (ED) staff, a lack of standard pediatric drug dosing and formulations,5 weight-based dosing,6,7 verbal orders, a hectic environment with frequent interruptions,8 a lack of clinical pharmacists on the ED care team,9,10 inpatient boarding status,11 the use of information technology systems that lack pediatric safety features,12 and numerous transitions in care. In addition, the vast majority of pediatric patients seeking care in EDs are not seen in pediatric hospitals but rather in community hospitals, which may treat a low number of pediatric patients.13 Studies also outline the problem of medication errors in children in the prehospital setting. A study of 8 Michigan emergency medical services agencies revealed errors for commonly used medications, with up to one-third of medications being dosed incorrectly.14 Medication error rates reported from single institutions with dedicated pediatric EDs range from 10% to 31%,15,16 and in a study from a pediatric tertiary care center network, Shaw et al6 showed that medication errors accounted for almost 20% of all incident reports, with 13% of the medication errors causing patient harm. The authors of another study examined medication errors in children at 4 rural EDs in northern California and found an error rate of 39%, with 16% of these errors having the potential to cause harm.17 The following discussion adds to the broad topic of medication safety by introducing specific opportunities unique to pediatric patients within EDs to facilitate local intervention on the basis of institutional experience and resources.

Strategies for Improvement

A multidisciplinary expert panel was convened by the Emergency Medical Services for Children program and the American Academy of Pediatrics (AAP), through its Committee on Pediatric Emergency Medicine, to discuss challenges related to pediatric medication safety in the emergency setting. The panel included emergency care providers, nurses, pharmacists, electronic health record industry representatives, patient safety organization leaders, hospital accreditation organizations, and parents of children who suffered ADEs. The panel outlined numerous opportunities for improvement, including raising awareness of risks for emergency care providers, trainees, children, and their families; developing policies and processes that support improved pediatric medication safety; and implementing best practices to reduce pediatric ADEs. Specific strategies discussed by the panel, as well as recent advances in improving pediatric medication safety, are described.

Decreasing Pediatric Medication Prescribing Errors in the ED

Computerized Physician Order Entry

Historically, the majority of pediatric medication errors were associated with the ordering phase of the medication process. Specific risks related to pediatric weight-based dosing include not using the appropriate weight,6 performing medication calculations based on pounds instead of the recognized standard of kilograms,6 and making inappropriate calculations, including tenfold dosing errors.1820 Childhood obesity introduces further opportunity for dosing error. In addition to the lack of science to guide medication dosing in patients with obesity,21 frequent underdosing22 is reported, and currently available resuscitation tools are commonly imprecise.23 Furthermore, there are limited opportunities for prescription monitoring or double-checking in the ED setting, and many times calculations are performed in the clinical area without input from a pharmacist.9 The implementation of computerized physician order entry (CPOE) and clinical decision support (CDS) with electronic prescribing have reduced many of these errors, because most CPOE systems obviate the need for simple dose calculation. However, CPOE systems have not fully eliminated medication errors. Commercial or independently developed CPOE systems may fail to address critical unique pediatric dosing requirements.12,24 Kilogram-only scales are recommended for obtaining weights, yet conversion to pounds either by the operator or electronic health record may introduce opportunity for error into the system. In addition, providers may override CDS, despite its proven success in reducing errors.16,25 Prescribers frequently choose to ignore or override CDS prescribing alerts, with reported override rates as high as 96%.26 Allowing for free text justification to override alerts for nonformulary drugs may introduce errors. The development of an override algorithm can help reduce user variability.27 As the use of CPOE increases, one can expect that millions of medication errors will be prevented.28 For EDs that do not use CPOE, preprinted medication order forms have been shown to significantly reduce medication errors in a variety of settings and serve as a low-cost substitute for CPOE.2932

Standardized Formulary

The Institute of Medicine (now the National Academy of Medicine) recommends development of medication dosage guidelines, formulations, labeling, and administration techniques for the pediatric emergency care setting.5 Unfortunately, there are currently no universally accepted, pediatric-specific standards with regard to dose suggestion and limits, and dosing guidelines and alerts found in CPOE are commonly provided by third-party vendors that supply platforms to both children’s and general hospitals. The development of a standard pediatric formulary, independent of an adult-focused system, can reduce opportunities for error by specifying limited concentrations and standard dosage of high-risk and frequently used medications, such as resuscitation medications, vasoactive infusions, narcotics, and antibiotics, as well as look-alike and sound-alike medications.33 A standard formulary will allow for consistent education during initial training and continuing medical education for emergency care providers, creating a consistent measure of provider competency. At least 1 large hospital organization has successfully implemented this type of change.34 In addition, the American Society of Health-System Pharmacists is working with the Food and Drug Administration to develop and implement national standardized concentrations for both intravenous and oral liquid medications.35

ED Pharmacists

Currently, many medications are prepared and dispensed in the ED without pharmacist verification or preparation because many EDs lack consistent on-site pharmacist coverage.9,36 In a survey of pharmacists, 68% reported at least 8 hours of ED coverage on weekdays, but fewer than half of EDs see this support on weekends, with a drastic reduction in coverage during overnight and morning hours.37 The American College of Emergency Physicians (ACEP) supports the integration of pharmacists within the ED team, specifically recognizing the pediatric population as a high-risk group that may benefit from pharmacist presence.38 The Emergency Nurses Association (ENA) supports the role of the emergency nurse as well as pharmacy staff to efficiently complete the best possible medication history and reduce medication discrepencies.39,40 The American Society of Health-System Pharmacists suggests that ED pharmacists may help verify and prepare high-risk medications, be available to prepare and double-check dosing of medications during resuscitation, and provide valuable input in medication reconciliation, especially of medically complex children whose medications and dosing may be unknown to ED staff and who present without a medication list or portable emergency information form.41 Medically complex patients typify the difficulty with medication reconciliation, with an error rate of 21% in a tertiary care facility.42 In this study, no 1 source from the parent, pharmacy, and primary provider group was both available and appropriately sensitive or specific in completing medication reconciliation. Pharmacist-managed reconciliation has had a positive impact for admitted pediatric patients and may translate to the emergency setting.43,44 ED pharmacists can also help monitor for ADEs, provide drug information, and provide information regarding medication ingestions to both providers and patients and/or families.45

Dedicated pharmacists can be integrated through various methods, such as hiring dedicated pharmacy staff for the ED,7 having these staff immediately available when consulted, or having remote telepharmacy review of medication orders by a central pharmacist.46,47 Although further research is needed on the potential outcomes on medication safety and return on investment when a pharmacist is placed in the ED, current experience reveals improvements in medication safety when a pharmacist is present.48 Studies from general EDs reveal significant cost savings as well,49 with the authors of 1 study in a single urban adult ED identifying more than $1 million dollars of cost avoidance in only 4 months.50

Training in Pediatric Medication Safety

Dedicated training in pediatric medication safety is highly variable in the curricula of professional training programs in medical, nursing, and pharmacy schools.51 Although national guidelines support the training of prehospital personnel with specific pediatric content and safety and error-reduction training,52 a nearly 35% prehospital medication error rate for critical medications for pediatric patients remains.14 At the graduate medical education level, the curricula of pediatric and emergency medicine residency programs and pediatric emergency medicine fellowship programs do not define specific requirements for pediatric medication safety training.5355 The same is true for pharmacy programs.56 Although schools of pharmacy include pediatric topics in their core curricula, pediatric safety advocates believe there is an opportunity for enhanced and improved training.57

Experts in pediatric emergency care from the multidisciplinary panel recommend development of a curriculum on pediatric medication safety that could be offered to all caregivers of children in emergency settings. A standard curriculum may include content such as common medication errors in children, systems-improvement tools to avoid or abate errors, and the effects of developmental differences in pediatric patients. Demonstrating competency on the basis of this curriculum is 1 means by which institutions may reduce risks of medication errors.

Decreasing Pediatric Medication Administration Errors in the ED

The dispensing and administration phases serve as final opportunities to optimize medication safety. Strategies to reduce errors include standardizing the concentrations available for a given drug, having readily available and up-to-date medication reference materials, using premixed intravenous preparations when possible, having automated dispensing cabinets with appropriate pediatric dosage formulations, using barcoded medication administration,58 having pharmacists and ED care providers work effectively as a team, and having policies to guide medication use.59,60 Although yet to be studied in the ED environment, smart infusion pumps have shown promise in other arenas in reducing administration errors for infusions.61

Nurses are held accountable by each state’s nurse practice act for the appropriateness of all medications given. Nursing schools teach the 5 rights of medication administration: the right patient, the right medication, the right dose, the right time, and the right route.62 Elliott and Liu63 expand the 5 rights to include right documentation, right action, right form, and right response to further improve medication safety. Simulated medication administration addresses opportunities beyond those captured within these rights and may have implications within the ED.64 Additionally, given the association of medication preparation interruptions and administration errors,65 the use of a distraction-free medication safety zone has been shown to enhance medication safety.66,67 Implementation of an independent 2-provider check process for high-alert medications, as suggested by The Joint Commission, also reduces administration errors.68 Both the Institute for Safe Medication Practices and The Joint Commission provide excellent guidance on these topics.69

Decreasing Pediatric Medication Errors in the Home

Recognizing and addressing language barriers and health literacy variability in the ED can affect medication safety in the home. Nonstandardized delivery devices continue to be used in the home, and dosing error rates of greater than 40% are reported.70 Advanced counseling and instrument provision in the ED are proven to decrease dosing errors at home.71 Pictograms provided to aide in medication measurement have also been shown to decrease errors and may be considered as part of discharge instructions.72 The AAP supports policy on the use of milliliter-only dosing for liquid medications used in the home and suggests that standardized delivery devices be distributed from the ED for use with these medications.73 As the body of literature regarding health literacy evolves, further addressing these issues in real time may influence out-of-hospital care.

Summary

Pediatric medication safety requires a multidisciplinary approach across the continuum of emergency care, starting in the prehospital setting, during emergency care, and beyond. Key areas for medication safety specific to pediatric care in the ED include the creation of standardized medication dosing guidelines, better integration and use of information technology to support patient safety, and increased education standards across health care disciplines. The following is a list of specific recommendations that can lead to improved pediatric medication safety in the emergency care setting.

Recommendations

  1. Create a standard formulary for pediatric high-risk and commonly used medications;

  2. standardize concentrations of high-risk medications;

  3. reduce the number of available concentrations to the smallest possible number;

  4. provide recommended precalculated doses;

  5. measure and record weight in kilograms only;

  6. use length-based dosing tools when a scale is unavailable or use is not feasible;

  7. implement and support the availability of pharmacists in the ED;

  8. use standardized order sets with embedded best practice prescribing and dosing range maximums;

  9. promote the development of distraction-free medication safety zones for medication preparation;

  10. implement process screening, such as a 2-provider independent check for high-alert medications;

  11. implement and use CPOE and CDS with pediatric-specific kilogram-only dosing rules, including upper dosing limits within ED information systems;

  12. encourage community providers of children with medical complexity to maintain a current medication list and an emergency information form to be available for emergency care;

  13. create and integrate a dedicated pediatric medication safety curriculum into training programs for nurses, physicians, respiratory therapists, nurse practitioners, physician assistants, prehospital providers, and pharmacists;

  14. develop tools for competency assessment;

  15. dispense standardized delivery devices for home administration of liquid medications;

  16. dispense milliliter-only dosing for liquid medications used in the home;

  17. employ advanced counseling such as teach-back when sharing medication instructions for home use; and

  18. use pictogram-based dosing instruction sheets for use of home medications.

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No more sweet tooth? Scientists switch off pleasure from food in brains of mice


Altering activity in brain’s emotion center can eliminate the natural craving for sweet; findings could inform treatments for eating disorders

New research in mice has revealed that the brain’s underlying desire for sweet, and its distaste for bitter, can be erased by manipulating neurons in the amygdala, the emotion center of the brain. The research points to new strategies for understanding and treating eating disorders including obesity and anorexia nervosa.

Brain illustration

New research in mice has revealed that the brain’s underlying desire for sweet, and its distaste for bitter, can be erased by manipulating neurons in the amygdala, the emotion center of the brain.

The study showed that removing an animal’s capacity to crave or despise a taste had no impact on its ability to identify it. The findings suggest that the brain’s complex taste system — which produces an array of thoughts, memories and emotions when tasting food — are actually discrete units that can be individually isolated, modified or removed all together. The research points to new strategies for understanding and treating eating disorders including obesity and anorexia nervosa.

The research was published today in Nature.

“When our brain senses a taste it not only identifies its quality, it choreographs a wonderful symphony of neuronal signals that link that experience to its context, hedonic value, memories, emotions and the other senses, to produce a coherent response,” said Charles S. Zuker, PhD, a principal investigator at Columbia’s Mortimer B. Zuckerman Mind Brain Behavior Institute and the paper’s senior author.

Today’s study builds upon earlier work by Dr. Zuker and his team to map the brain’s taste system. Previously, the researchers revealed that when the tongue encounters one of the five tastes — sweet, bitter, salty, sour or umami — specialized cells on the tongue send signals to specialized regions of the brain so as to identify the taste, and trigger the appropriate actions and behaviors.

To shed light on that experience, the scientists focused on sweet and bitter taste and the amygdala, a brain region known to be important for making value judgments about sensory information. Previous research by Dr. Zuker, a professor of biochemistry and molecular biophysics and of neuroscience and a Howard Hughes Medical Institute Investigator at Columbia University Irving Medical Center, and others showed that the amygdala connects directly to the taste cortex.

“Our earlier work revealed a clear divide between the sweet and bitter regions of the taste cortex,” said Li Wang, PhD, a postdoctoral research scientist in the Zuker lab and the paper’s first author. “This new study showed that same division continued all the way into the amygdala. This segregation between sweet and bitter regions in both the taste cortex and amygdala meant we could independently manipulate these brain regions and monitor any resulting changes in behavior.”

The scientists performed several experiments in which the sweet or bitter connections to the amygdala were artificially switched on, like flicking a series of light switches. When the sweet connections were turned on, the animals responded to water just as if it were sugar. And by manipulating the same types of connections, the researchers could even change the perceived quality of a taste, turning sweet into an aversive taste, or bitter into an attractive one.

In contrast, when the researchers instead turned off the amygdala connections but left the taste cortex untouched, the mice could still recognize and distinguish sweet from bitter, but now lacked the basic emotional reactions, like preference for sugar or aversion to bitter.

“It would be like taking a bite of your favorite chocolate cake but not deriving any enjoyment from doing so,” said Dr. Wang. “After a few bites, you may stop eating, whereas otherwise you would have scarfed it down.”

Usually, the identity of a food and the pleasure one feels when eating it are intertwined. But the researchers showed that these components can be isolated from each other, and then manipulated separately. This suggests that the amygdala could be a promising area of focus when looking for strategies to treat eating disorders.

In the immediate future, Drs. Zuker and Wang are investigating additional brain regions that serve critical roles in the taste system. For example, the taste cortex also links directly to regions involved in motor actions, learning and memory.

“Our goal is to piece together how those regions add meaning and context to taste,” said Dr. Wang. “We hope our investigations will help to decipher how the brain processes sensory information and brings richness to our sensory experiences.”

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Age related BP targets for chronic kidney disease patients work better


A cautious approach to lowering blood pressure (BP) in elderly patients with chronic kidney disease (CKD) is recommended, said US-based researchers. Treatment of hypertension in younger patients with CKD can follow current clinical guidelines, they added.

“Hypertension affects almost all patients with CKD, and is one of the few conditions that is treatable with a wide array of medications,” said lead author Professor Casaba P. Kovesdy, from the Division of Nephrology, Memphis Veterans Affairs Medical Center, Memphis, Tennessee, US.

Kovesdy and team examined systolic BP (SBP) and diastolic BP (DBP) with all-cause mortality, together with the incidence of chronic heart disease (CHD), ischaemic stroke, and end stage renal disease (ESRD) in 339,887 patients with CKD. [Clin J Am Soc Nephrol 2016;doi:10.2215/CJN.08660815]

During the 4.8 year median follow-up 100,763 patients died (95 percent confidence interval [CI], 62.6- 63.4). Mortality rates were high in older SBP patients. SBP ≥ 140mmHg and <120 mmHg was associated with higher mortality rates across all age groups. Lowest mortality was seen in SBP 120-139 mmHg for patients <80 years, and SBP 120-159 mmHg for patients ≥80 years.

Compared to SBP of 130-139 mmHg, SBP ≥170mmHg in patients aged <50, 50-59, 60-69, 70-79, and ≥80 years were adjusted hazard ratio [aHR], 1.95, 95 percent CI, 1.34-2.84; aHR, 2.01, 95 percent CI, 1.75-2.30; aHR, 1.68, 95 percent CI, 1.49-1.89; aHR, 1.39, 95 percent CI, 1.25-1.54; and aHR, 1.30, 95 percent CI, 1.17-1.44, respectively.

Lower DBP was associated with high mortality. DBP of 70-79 mmHg in patients <50 years and 80-89 mmHg in patients ≥50 years had the lowest mortality.

CHD was experienced in 9,450 patients during the study period (95 percent CI, 9.6-10.0). Higher SBP was associated with higher CHD rates in patients <80 years. However, lowest CHD rates were associated with SBP<110 mmHg in patients <70 years and SBP<140 mmHg in patients ≥70 years. DBP on the other hand had no association with CHD.

Ischaemic stroke was experienced by 14,557 patients (95 percent CI, 10.2-10.6). While higher SPB was associated with higher stroke rates across all age groups, DBP showed no association. Lowest stroke risk was seen in patients with SBP <100mmHg.

ESRD rates were found to be lower in older individuals compared to younger patients. ESRD was seen in 5,161 patients (95 percent CI, 3.2-3.3). DBP was found to have no association with ESRD, but high SBP was associated with high ESRD incidence. Patients <80 years with SBP ≥170mmHg had high ESRD risk, but SBP <170mmHg in this age group had no associated risk.

“Our results reinforce the significant association of elevated SBP with all the studied outcomes but suggest weak association in the elderly, especially in patients aged ≥80years,” said Kovesdy. “The best outcomes were seen with SBP of 120-130 mmHg in patients <80 years and of 120-159 mmHg in those ≥80years.”

In a separate editorial, Assistant Professor Jessica W. Weiss from the Division of Nephrology and Hypertension, Oregon Health and Science University, Portland, Oregon, US said that the study by Kovesdy and team added to the collective understanding of the relationship between BP and a wide range of various clinical outcomes in older adults with CKD, a group rarely studied. This, she said, may be useful in guiding the design of future studies in this area. [Clin J Am Soc Nephrol 2016;doi:10.2215/CJN.03100316]

“These results may also add a note of caution to newfound enthusiasm for lower BP targets after the release of the SPRINT* via the suggestion that harm may persist at upper and lower extremes of BP among populations more comorbid and complex than those evaluated in the setting of a clinical trial,” said Weiss.

 

Evolocumab plus statin potentially reduces atherosclerosis progression in GLAGOV study


The addition of evolocumab to statin therapy in individuals with angiographic coronary disease appeared to encourage coronary atherosclerosis regression, as demonstrated in the GLAGOV* trial presented at the Scientific Sessions of the American Heart Association (AHA 2016) held in New Orleans, Louisiana, US.

In comparison with patients on statin alone who experienced a nonsignificant 0.05 percent increase in percent atheroma volume (PAV), those on combined therapy of statin and evolocumab had a 0.95 percent reduction in PAV (difference, -1.0 percent, 95 percent confidence interval [CI], -1.8 to -0.64 percent; p<0.001). Normalized total atheroma volume (TAV) decreased by 0.9 mm3 (nonsignificant) in those on statin alone compared with 5.8 mm3 in those on statin and evolocumab (difference, -4.9 mm3, 95 percent CI, -7.3 to -2.5; p<0.001). [AHA 2016, LBCT 03; JAMA 2016;doi:10.1001/jama.2016.16951]

Plaque regression occurred in a greater number of patients on evolocumab and statin compared with those on statin alone (64.3 percent vs 47.3 percent; difference, 17.0 percent, 95 percent CI, 10.4 to 23.6 percent; p<0.001 for PAV and 61.5 percent vs 48.9 percent; difference, 12.5 percent, 95 percent CI, 5.9 to 19.2 percent; p<0.001 for TAV).

“We are really reducing plaque burden in the coronaries if we can get [low-density lipoprotein cholesterol (LDL-C)] down to these very low levels,” said study chair Dr Steven Nissen from the Department of Cardiovascular Medicine at the Cleveland Clinic, Cleveland, Ohio, US, who presented the findings. “It turns out that a little bit of change in plaque volume translates into a very big change in plaque behaviour.”

“[These findings] suggest a new era in lipid management,” said discussant Dr Raul Santos from the University of São Paulo, Brazil.

Evolocumab appeared to be well tolerated with comparable incidences of injection site reactions (0.4 percent vs 0 percent), myalgia (7.0 percent vs 5.8 percent), neurocognitive events (1.4 percent vs 1.2 percent), and new onset diabetes (3.6 percent vs 3.7 percent) for evolocumab plus statin vs statin monotherapy, respectively.

In this double-blind, placebo-controlled, multicentre trial, participants (n=968, mean age 59.8 years; 72 percent male) with angiographic coronary disease, LDL-C levels ≥80 mg/dL or 60–80 mg/dL with additional high-risk features, and on stable statin therapy were randomized to receive monthly subcutaneous injections of the proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitor, evolocumab (420 mg) or placebo for 76 weeks. After angiography, participants underwent intravascular ultrasound (IVUS) of the same artery at baseline and at week 78.

“Both the primary and secondary IVUS efficacy measures showed atherosclerosis regression … in patients treated with the combination of evolocumab and statins and absence of regression in patients treated with a statin alone,” said study lead investigator Dr Steven Nicholls, also from the Cleveland Clinic. “These findings provide evidence that PCSK9 inhibition produces incremental benefits on coronary disease progression in statin-treated patients.”

“Over the last 4 decades, evidence has accumulated suggesting that optimal LDL levels for patients with coronary disease may be much lower than commonly achieved. While we await large outcome trials for PCSK9 inhibitors, the GLAGOV trial provides intriguing evidence that clinical benefits may extend to LDL-C levels as low as 20 mg/dL,” said Nissen, who acknowledged the limitations of the trial such as the small number of patients and short treatment period. “IVUS is a useful measure of disease activity, but the critical determination of benefit and risk will require completion of large outcome trials currently underway,” he said.

Other factors that could potentially influence disease progression in the setting of very low LDL-C levels also need to be investigated, said Nicholls.

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Managing hypertension may prevent chronic kidney disease


Health education combined with general practitioner (GP) training in managing blood pressure delayed decline of kidney function and lowered the risk of death from kidney failure in individuals with hypertension, according to an extended analysis of the COBRA* study.

“Our findings indicate that public health interventions using effective lifestyle modification approaches and training of providers in a primary care setting can yield long-term benefits for preserving kidney function,” said lead author Dr. Tazeen Jafar, a professor of Health Services and Systems Research at the Duke-NUS Graduate Medical School in Singapore, Singapore.

The study included 1,271 hypertensive individuals aged ≥40 years from low-income communities in Pakistan. The participants were randomly assigned to a control group, which received standard care, or an intervention group, which received health education emphasising healthy lifestyle and adherence to antihypertensive medication, and/or care from GP trained in hypertension management for 2 years. [Clin J Am Soc Nephrol 2016;doi:10.2215/CJN.05300515]

The participants were evaluated for changes in kidney function from baseline to 7 years after the start of intervention.

Kidney function, measured as the estimated glomerular filtration rate (eGFR), of the intervention group did not changed significantly (-0.3 ml/min per 1.73m2, 95 percent confidence interval [CI], -3.5 to 2.9 ml/min per 1.73m2) after 7 years, compared with the control group, which saw a -3.6 ml/min per 1.73m2 decline in eGFR (95 percent CI, -5.7 to -2.0 ml/min per 1.73m2) (p=0.01).

Participants receiving intervention were half as likely as participants on standard care to experience a >20 percent decline in kidney function (adjusted risk ratio [adjRR], 0.53, 95 percent CI, 0.29-0.96; p=0.04).

Also, the risk of death from kidney failure or >20 percent kidney function decline was significantly lower in the intervention group compared with control group (adjRR, 0.47, 95 percent CI, 0.25-0.89).

“Blood pressure control is a cornerstone of management to both prevent the onset and delay the progression of CKD,” said Drs. Min Jun and Brenda Hemmelgarn from the Department of Medicine at the University of Calgary in Alberta, Canada in a separate editorial. [Clin J Am Soc Nephrol 2016;11:932–934]

“Current clinical guidelines widely advocate blood pressure reduction strategies, including both pharmacologic and lifestyle interventions.”

Previous studies showed that improvement in diet and exercise had beneficial effects on cardiometabolic parameters and preserving kidney function. [Cochrane Database Syst Rev 2011;(10): CD003236, Nephrology (Carlton) 2015;20:61–67]

These simple interventions could be implemented in low- and middle-income countries to help prevent chronic kidney diseases (CKD), suggested Jafar.

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Malay ethnicity, smoking, hyperlipidaemia predict risk of coronary calcification


Malay ethnicity, male gender, smoking and having hyperlipidaemia are associated with an increased risk of coronary calcification, according to a study presented at the Asian Pacific Society of Cardiology (APSC) Congress 2018 in Taipei, Taiwan.

“Coronary artery calcium (CAC) is highly associated with the presence of coronary atherosclerotic plaque that has prognostic value towards cardiovascular events,” lead author Shu Yun Heng said. “It has shown that CAC varies among different ethnic groups in the same age and gender.”

Multivariate analysis of 16,546 individuals revealed that CAC increased with increasing age (adjusted odds ratio [AOR], 1.13; 95 percent CI, 1.13–1.14). Compared with women, men had higher CAC score across all ages (AOR, 3.70; 3.41–4.02).

Individuals of Malay ethnicity generally had higher CAC compared with those of Chinese ethnicity (AOR, 1.37; 1.16–1.63), after adjusting for confounding variables. In addition, CAC was also higher in smokers than nonsmokers (AOR, 13.29; 1.43–123.87) and among individuals with hyperlipidaemia (AOR, 1.62; 1.02–2.58).

These results are consistent with those of the Multi-Ethnic Study of Atherosclerosis (MESA), which found that men had greater calcium levels than women, and calcium amount and prevalence were steadily higher with increasing age. Researchers also found significant differences in calcium by race, and these associations differed across age and gender. [Circulation 2006;113:30-73]

A prospective cohort study, MESA is designed to assess subclinical cardiovascular disease (CVD) in a multiethnic cohort free of clinical CVD. A total of 6,110 patients (mean age 62 years; 53 percent women) participated in the study. [Circulation 2006;113:30-73]

The MESA public website (http://www.mesa-nhlbi.org) provides an interactive form that allows one to enter an age, gender, race/ethnicity, and CAC score to obtain a corresponding estimated percentile.

Bild and colleagues, in one publication of the MESA results, also found ethnic differences in the presence and quantity of coronary calcification that were not explained by coronary risk factors. [Circulation 2005;111:1313-1320]

“Identification of the mechanism underlying these differences would further our understanding of the pathophysiology of coronary calcification and its clinical significance,” said Bild, adding that “[d]ata on the predictive value of coronary calcium in different ethnic groups are needed.”

Furthermore, data from another study focusing on the prognostic value of CAC in a large, ethnically diverse cohort for the prediction of all-cause mortality support a growing body of evidence noting substantial differences in cardiovascular risk by ethnicity. [J Am Coll Cardiol 2018;doi:10.1016/j.jacc.2007.03.066]

In this present retrospective study, Heng and colleagues assessed the distribution of CAC in a multiethnic cohort between ages 35–84 years from a single tertiary institution, National Heart Centre Singapore, between 2007 and 2017. Participants were 64 percent men and had a mean age of 55 years. CAC was determined by 320 Multi-Detector Row CT.

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What, how, when of using NOACs in practice


Dr Chan Yi-Hsin

When making practical decision on using non-vitamin K antagonist oral anticoagulants (NOACs), several factors should be considered such as age, renal function, and risk of bleeding, according to a presentation at the APSC Congress 2018.

The Asia Pacific Heart Rhythm Society (APHRS) 2017 consensus paper states that “for Asian patients with nonvalvular atrial fibrillation (AF), standard-dose NOACs are the default doses of choice for stroke prevention unless label guidance recommends low-dose regimens.” [J Arrhythm 2017;33:345-367]

“Aspirin is not recommended solely for stroke prevention in AF,” said Dr Chan Yi-Hsin of Chang Gung Memorial Hospital, Linkou, Taiwan.

The recommendations from APHRS are generally aligned with the ACC* and ESC** guidelines, he noted, which indicate that low-risk patients (defined by a CHAD2DS2-VASc=0 for male and =1 for female) do not require antithrombotics. On the other hand, higher-risk patients (CHAD2DS2-VASc ≥2 for all or =1 for male) were recommended to be further assessed with the SAMeTT2R2 score to guide the choice of anticoagulants — NOACs are preferred if the final score is ≥3. [J Arrhythm 2017;33:345-367]

How and what to select?

In selecting which NOAC to use, clinicians need to consider the CHAD2DS2-VASc score, age, renal and liver function, risk of bleeding, and concurrent medications a patient is receiving, Chan pointed out. [APSC 2018, session S047-04]

If CHAD2DS2-VASc=0/1, dabigatran or apixaban can be considered, based on findings from the RELY and ARISTOTLE trials which involved 30–34 percent of lower-risk patients in the overall study population. [N Engl J Med 2009;361:1139-1151; N Engl J Med 2010;363:1875-1876; N Engl J Med 2011;365:981-992] In higher-risk patients, the ENGAGE AF-TIMI 48 trial involving 77.4 percent of patients with CHAD2DS2-VASc=2 suggests the use of edoxaban in such patients, while the ROCKET AF study comprising 87 percent of patients with CHAD2DS2-VASc ≥3 indicates that rivaroxaban be used in these patients. [N Engl J Med 2011;365:883-891; N Engl J Med 2013;369:2093-2104]

Nonetheless, Chan was quick to point out that there are no head-to-head trials comparing the different NOACs so far, and the above suggestions are based on review of the various randomized controlled trials comparing each NOAC with warfarin.

When selecting NOAC in elderly patients (aged ≥75 years), a review study on phase III randomized clinical trials (RCTs) suggests that the risk of bleeding was reduced with apixaban 5 mg BID vs warfarin but the converse was seen (ie, warfarin was favoured) when compared with rivaroxaban 20 mg QD or dabigatran 110/150 mg BID in elderly patients. [Best Pract Res Clin Haematol 2013;26:215-224]

As different NOAC has different renal excretion rate, AF patients with impaired renal function (eGFR*** <50 mL) can consider dabigatran up to 150 mg with regards to efficacy (in terms of reduction in stroke rates), said Chan. [N Engl J Med 2009;361:1139-1151] However, in terms of safety outcome, apixaban can be considered in these patients as previous finding has shown a greater extent of reduction in major bleeding risk with apixaban vs warfarin. [N Engl J Med 2011;365:981-992]

“NOACs can [also] be used in patients with mild or moderate liver impairment (Child-Pugh categories A and B), with no dose reduction required for any of the NOAC in AF patients with Child-Pugh category A impairment,” said Chan. “NOACs are not recommended for those in Child-Pugh category C.” [Eur Heart J 2018;39:1330-1393]

One should also consider drug-drug interactions of NOACs with other medications a patient is taking, advised Chan. For example, in AF patients who are also taking HIV protease inhibitor or anti-epileptic drugs (such as carbamazepine, phenobarbital, phenytoin), all NOACs are contraindicated. [J Formos Med Assoc 2016;115:893-952; J Arrhythm 2017;33:345-367]

When to stop and restart?

“Renal function and surgical factors [ie, bleeding risk for surgery] help to determine when to discontinue and restart a NOAC for elective surgery,” said Chan.

According to the APHRS, TSOC, and THRS# guidelines, AF patients with normal renal function can stop any of the NOAC ≥24 hours before an elective surgical intervention classified to be of low bleeding risk and ≥48 hours for high bleeding risk. However, in AF patients with renal impairment, a longer duration of NOAC discontinuation before an elective surgery needs to be considered for those on dabigatran. [J Formos Med Assoc 2016;115:893-952; J Arrhythm 2017;33:345-367]

“Heparin/LMWH## bridging is generally not necessary for NOACs. NOAC is uninterrupted when performing AF catheter ablation,” said Chan.

“Generally, NOACs can be restarted 24 hours post-procedure with low-bleeding risk, and 48–72 hours post-procedure with high-bleeding risk. For procedure in which immediate and complete haemostasis can be achieved (eg, pacemaker implantations and skin surgery), NOACs can be resumed 6–8 hours after the interventions,” he added, citing recommendations from the ESC, APHRS, TSOC, and THRS guidelines. [Eur Heart J 2018;39:1330-1393; J Formos Med Assoc 2016;115:893-952; J Arrhythm 2017;33:345-367]

Bleeding management

“For non-life-threatening major bleeding, reversal agent is generally not necessary … these can be managed with supporting care,” said Chan. [Eur Heart J 2018;39:1330-1393]

For life-threatening major bleeding, idarucizumab is the specific reversal agent for dabigatran while andexanet alpha can be used to reverse factor Xa inhibitors such as apixaban, rivaroxaban, and edoxaban, he stated.

 

 

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Dapagliflozin drives HbA1c, SBP, and weight down in DERIVE


Dr Siew-Pheng Chan.

The use of the sodium/glucose cotransporter 2 (SGLT-2) inhibitor dapagliflozin in patients with type 2 diabetes (T2D) and moderate renal impairment provides benefits beyond glucose lowering, with no new safety signals, in the phase III DERIVE* study.

At 6 months, the primary endpoint of mean reduction in HbA1c level was greater by 0.34 percent in patients treated with dapagliflozin vs placebo (p< 0.001). There were also greater reductions in systolic blood pressure (SBP, 3.1 mm Hg; p<0.05) and mean body weight (1.25 percent, p< 0.001) with dapagliflozin. (APSC 2018, abstract S105-01)

“Dapagliflozin induces glycosuria and lowers blood glucose. However, the glycaemic efficacy of dapagliflozin is attenuated in patients with moderate renal impairment, for example in stage 3 CKD, because less glucose is cleared in the kidney in this group,” said Dr Siew-Pheng Chan, consultant endocrinologist at Subang Jaya Medical Centre in Subang Jaya, Malaysia, who is unaffiliated with the study.

Researchers led by Dr Paola Fioretto of the University of Padova in Padua, Italy conducted the DERIVE study to compare the efficacy and safety of dapagliflozin vs placebo in 321 patients with T2D (HbA1c of 7 –11 percent) and moderate renal impairment (stage 3A chronic kidney disease (CKD), estimated glomerular filtration rate (eGFR), 45 to <60 mL/min/1.73m2). Patients were randomized to either dapagliflozin 10 mg (n=160) or placebo (n=161) over 6 months. Randomization was stratified by background glucose-lowering medication. Both groups had similar baseline characteristics.

At 6 months, treatment with dapagliflozin resulted in a significant reduction in mean HbA1c (-0.37 percent vs -0.03 percent for placebo) and mean body weight (-3.17 vs -1.92 kg, respectively) from baseline. The mean fasting plasma glucose was also significantly reduced with dapagliflozin (-21.46 vs -4.87 mg/dL for placebo) as was mean SBP (-4.8 vs -1.7 mm Hg, respectively) from baseline to 6 months.

In terms of safety, mean eGFR was reduced with dapagliflozin (-3.23 mL/min/1.73m2) vs placebo (-0.63 mL/min/1.73m2). Urinary tract infection and genital infection were the most common adverse events of interest reported. Overall, the safety profile of dapagliflozin was consistent with previous reports seen for T2D. No bone fractures or amputations were reported.

Dapagliflozin is currently indicated as an adjunct to diet and exercise to improve glycaemic control in adults with T2D. Dapagliflozin remains contraindicated in patients with an eGFR <30 mL/min/1.73 m².

 

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