research paper of 2021

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HBR’s Most-Read Research Articles of 2021

• Dagny Dukach

A look back at the insights that resonated most with our readers.

What will it take to make work better? Over the past year, HBR has published a wide array of research-backed articles that explore topics ranging from retaining employees to overcoming meeting overload to fostering gender equity in the workplace. In this end-of-year roundup, we share key insights and trends from our most-read research articles of 2021.

As the workplace rapidly transforms in the wake of the pandemic, social movements, and more, a fundamental question remains: How can we ensure we’re making work better — for employees, organizations, and society at large?

• Dagny Dukach is a former associate editor at Harvard Business Review.

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Research Topics

Top 10 research topics from 2021.

Find the answers to your biggest research questions from 2021. With collective views of over 3.7 million, researchers explored topics spanning from nutritional immunology and political misinformation to sustainable agriculture and the human-dog bond .

Research Topics:

1. Infectious disease

• 1,643,000 views
• 29 articles

2. Nutritional immunology

• 768,000 views

3. Music therapy

• 268,000 views
• 44 articles

4. Political misinformation

• 219,000 views
• 11 articles

5. Plant science

• 198,000 views
• 15 articles

6. Sustainable agriculture

• 168,000 views
• 49 articles

7. Mental health

• 136,000 views
• 22 articles

8. Aging brains

• 134,000 views
• 18 articles

Benefits of human-dog interactions

• 229,000 views
• 13 articles

10. Mood disorders

• 102,000 views
• 12 articles

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• The BMJ Awards 2021:...

The BMJ Awards 2021: Research paper of the year

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This year’s winner was a landmark trial that changed practice worldwide in the treatment of covid-19, writes Matthew Limb

“Dexamethasone in hospitalized patients with covid-19,” by the Recovery Collaborative Group

The BMJ’s judges said this “landmark trial” had a “profound impact” on outcomes for people with covid-19 across the world. From the moment covid-19 appeared, the search was on for treatments that could improve survival, particularly in the sickest patients. The Recovery trial was the …

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• Last updated November 18, 2021
• In AI Origins & Evolution

Top Machine Learning Research Papers Released In 2021

• Published on November 18, 2021
• by Dr. Nivash Jeevanandam

Advances in machine learning and deep learning research are reshaping our technology. Machine learning and deep learning have accomplished various astounding feats this year in 2021, and key research articles have resulted in technical advances used by billions of people. The research in this sector is advancing at a breakneck pace and assisting you to keep up. Here is a collection of the most important recent scientific study papers.

Rebooting ACGAN: Auxiliary Classifier GANs with Stable Training

The authors of this work examined why ACGAN training becomes unstable as the number of classes in the dataset grows. The researchers revealed that the unstable training occurs due to a gradient explosion problem caused by the unboundedness of the input feature vectors and the classifier’s poor classification capabilities during the early training stage. The researchers presented the Data-to-Data Cross-Entropy loss (D2D-CE) and the Rebooted Auxiliary Classifier Generative Adversarial Network to alleviate the instability and reinforce ACGAN (ReACGAN). Additionally, extensive tests of ReACGAN demonstrate that it is resistant to hyperparameter selection and is compatible with a variety of architectures and differentiable augmentations.

This article is ranked #1 on CIFAR-10 for Conditional Image Generation.

For the research paper, read here .

For code, see here .

Dense Unsupervised Learning for Video Segmentation

The authors presented a straightforward and computationally fast unsupervised strategy for learning dense spacetime representations from unlabeled films in this study. The approach demonstrates rapid convergence of training and a high degree of data efficiency. Furthermore, the researchers obtain VOS accuracy superior to previous results despite employing a fraction of the previously necessary training data. The researchers acknowledge that the research findings may be utilised maliciously, such as for unlawful surveillance, and that they are excited to investigate how this skill might be used to better learn a broader spectrum of invariances by exploiting larger temporal windows in movies with complex (ego-)motion, which is more prone to disocclusions.

This study is ranked #1 on DAVIS 2017 for Unsupervised Video Object Segmentation (val).

Temporally-Consistent Surface Reconstruction using Metrically-Consistent Atlases

The authors offer an atlas-based technique for producing unsupervised temporally consistent surface reconstructions by requiring a point on the canonical shape representation to translate to metrically consistent 3D locations on the reconstructed surfaces. Finally, the researchers envisage a plethora of potential applications for the method. For example, by substituting an image-based loss for the Chamfer distance, one may apply the method to RGB video sequences, which the researchers feel will spur development in video-based 3D reconstruction.

This article is ranked #1 on ANIM in the category of Surface Reconstruction. 

EdgeFlow: Achieving Practical Interactive Segmentation with Edge-Guided Flow

The researchers propose a revolutionary interactive architecture called EdgeFlow that uses user interaction data without resorting to post-processing or iterative optimisation. The suggested technique achieves state-of-the-art performance on common benchmarks due to its coarse-to-fine network design. Additionally, the researchers create an effective interactive segmentation tool that enables the user to improve the segmentation result through flexible options incrementally.

This paper is ranked #1 on Interactive Segmentation on PASCAL VOC

Learning Transferable Visual Models From Natural Language Supervision

The authors of this work examined whether it is possible to transfer the success of task-agnostic web-scale pre-training in natural language processing to another domain. The findings indicate that adopting this formula resulted in the emergence of similar behaviours in the field of computer vision, and the authors examine the social ramifications of this line of research. CLIP models learn to accomplish a range of tasks during pre-training to optimise their training objective. Using natural language prompting, CLIP can then use this task learning to enable zero-shot transfer to many existing datasets. When applied at a large scale, this technique can compete with task-specific supervised models, while there is still much space for improvement.

This research is ranked #1 on Zero-Shot Transfer Image Classification on SUN

CoAtNet: Marrying Convolution and Attention for All Data Sizes

The researchers in this article conduct a thorough examination of the features of convolutions and transformers, resulting in a principled approach for combining them into a new family of models dubbed CoAtNet. Extensive experiments demonstrate that CoAtNet combines the advantages of ConvNets and Transformers, achieving state-of-the-art performance across a range of data sizes and compute budgets. Take note that this article is currently concentrating on ImageNet classification for model construction. However, the researchers believe their approach is relevant to a broader range of applications, such as object detection and semantic segmentation.

This paper is ranked #1 on Image Classification on ImageNet (using extra training data).

SwinIR: Image Restoration Using Swin Transformer

The authors of this article suggest the SwinIR image restoration model, which is based on the Swin Transformer . The model comprises three modules: shallow feature extraction, deep feature extraction, and human-recognition reconstruction. For deep feature extraction, the researchers employ a stack of residual Swin Transformer blocks (RSTB), each formed of Swin Transformer layers, a convolution layer, and a residual connection.

This research article is ranked #1 on Image Super-Resolution on Manga109 – 4x upscaling.

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• Classification , Deep Learning , Generative Adversarial Network , gradient boosting , Machine Learning , RGB , supervised learning , Unsupervised Learning

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125 Best Research Paper Topics of 2021

When you get into high school, you are not aware of the number of responsibilities you might have to face over your academics, making you feel clogged and exhausted, especially when writing and submitting research papers on time.

One of the most challenging parts of writing a research paper is to find a perfect topic to write. Luckily, we have done all the hard work for you and have created a list of 125 fascinating research paper topics.

For your further convenience, we have organized the topics into different categories covering a wide range of subjects so you can easily choose the best topic according to your interest and knowledge.

Besides the list of good research topics, I have also talked about selecting a good research topic and how you can use your subject to start writing an excellent paper.

How to Select a Perfect Research Paper Topic?

Before you start writing, you need to make sure you choose a great topic. Below mentioned are the three crucial factors to contemplate before selecting the best research paper topics.

Choosing a field, you are interested in

It is difficult to find a research paper topic because most high-school students are confused about selecting their major. However, you can always select an area of interest.

There are always specific research topics on trending. Many people seem interested in writing about the buzzing topics; never feel tempted or go with the crowd and make it your subject unless you genuinely have some interest in it.

There is enough information to foster your research.

Once you have chosen the best research paper topic and you're happy to write about it, it is still challenging to produce a good paper if there isn't enough information about the subject. 

This is possible for very particular or specialized topics, and sometimes some topics are too new to have enough research conducted on them at the moment. Simple topics will always have more than enough information to write a full-length paper. Writing a research paper on a topic that does not have enough information is extremely hard. Before you take up a topic, do primary research and make sure you have all the essential information to write your research paper.

The research paper fits your teacher guidelines. 

Always note down any specific requirements or restrictions your teacher may have implemented on some research topic ideas. If you are writing a research paper on a political science topic, deciding to write about technology’s impact on sports won’t be allowed. Still, there can be some sort of flexibility.

For example, if you want to write about the “Portrayal of minorities by Media” and your teacher wants you to write about “History,” you can combine both topics and develop something relevant. Like “How the portrayal of minorities by media go a long way back.” You can also use companies, like do my essay , to help you write your research paper.

For your convenience, we have organized the topics into different categories. It will also make it easier to find the type of research paper topics you're looking for.

Simple research paper topics

• How important is diversity within the team, and why?
• What makes one sport more accepted than another?
• How would the world be different without the discoveries of Albert Einstein?
• Rise of anime; what made anime admired worldwide?
• Is the traditional music of a country foremost than the international music that is popular around the world?
• What causes people to change their leisure time activities as they get older?
• What is the best way to deal with procrastination?
• What are hobbies more favored with children and adults in your area?
• Are there hobbies you can easily do in your own country but not so comfortable when you go to another country? Why?
• What are stereotypes of people from your country, and how true are those?

Interesting research paper topics

• How true is it that older people are wiser and correct, always right in their choices?
• Can technology cause a gap between generations?
• How different are friendships between men from friendships between women, and why?
• Can amusement parks have an educational motive aside from an entertaining one? 
• What things make people in your country happy?
• What are the pros and cons of plastic surgery?
• Does beauty, in general, decide how much a person will be happy and successful in life?
• What other common sayings such as “Actions speak louder than words” exist in your language, and what life lessons they teach?
• What makes Nordic regions happier and more prosperous than others?
• Ways to communicate better with family, friends, colleagues, and strangers?

Controversial topics for research paper

These topics might stimulate terrible responses from some people because most of these subjects are controversial and are likely to raise some issues. Be careful before writing about such topics.

• What is the context of all terrorist attacks in the world?
• How to deal with a large number of immigrants?
• How to prevent a rise in the number of homeless children?
• What is the proper punishment for serial killers and rapists?
• Will religion survive the future? Explain

Aggressive research topics

• Are video games the reason for more antisocial people?
• What makes communism the best political system in the world?
• How will a rise in the minimum wage help increase economic mobility?
• Should steroids be allowed in sports?
• What can things be done on an individual level to prevent cyberbullying?

Research topics by different fields of study

In different fields of study, you can tell your brain to perform innovatively. Here, you can carry out extensive research to put forward new opinions.

• What were the devastating impacts of British rule in India ? 
• What events led to the fall of the Roman Empire?
• Was it necessary to bomb Hiroshima and Nagasaki?
• Who was responsible for the Iran-Contra situation ? 
• What caused the Soviet Union to invade Afghanistan ?
• What are the important events in the history of Latin America? 
• How did Greece become a huge philosophical hub in ancient times?
• How did people study foreign languages before the 19th century?
• Who profited the most from wars in the Middle Ages?
• What caused Hitler's rise to power?

Sample History research papers

Environment 

• How deadly is the Earth’s climate change in the past few decades?
• How have previous oil spills changed regulations and cleaning methods?
• Make a detailed analysis of deforestation rates globally over a while.
• Impacts of Paris Climate Agreement on environment
• How to improve access to clean water around the world?
• Should developed countries rely more on nuclear energy?
• What to do to save amphibian species which are presently at risk of extinction?
• What impacts has climate change had on coral reefs?
• How are black holes created?
• Why has the number of natural disasters increased in the past few decades?

Sample Environment research papers 

• What can health issues be caused by emotional stress?
• What are the most effective ways to treat depression ?
• What are the advantages and drawbacks of the Keto diet?
• How do the healthcare plans of different countries vary from each other?
• How to lower blood pressure using natural herbs?
• Is it appropriate for parents to skip vaccination?
• How can you encourage obese people to change their lifestyles?
• What are the cons of genetically modified foods?
• Explain the history and impact of the HIV/AIDS epidemic.
• How much work out/ exercise should the average adult be getting each week?

Sample Health research papers

• How is business etiquette changed in the past decade?
• How can the understanding of culture change the way you do business?
• Who are the exceptional businessmen in the 21st century?
• Who are the exceptional businesswomen in the 21st century?
• What are the traits of team leaders, and how to become one?
• Why is the cause in the rise of the popularity of stock markets?
• What are the pros and cons of an all-female working environment?
• The difference in Islamic banking systems from traditional ones?
• What are the effects of gold and diamonds on the economy?
• How do offshore bank accounts work – the case of Panama papers?
• Analyze the history and future of self-driving vehicles.
• How the invention of drones changed surveillance and warfare methods?
• Why has social media made people less connected to reality?
• Rise of Artificial Intelligence? Explain
• Do smartphones improve or reduce workplace productivity?
• What are the most effective ways to use technology in the classroom?
• How is social media manipulating and causing depression?
• What is the history behind the Internet of Things?
• Can everything be solar-powered?
• What is the distinction between open and closed systems?

Sample Technology research papers

• Why did we stop believing in multiple gods?
• Are religion and spirituality connected?
• What is Karma?
• Why are teenagers less religious than older people?
• How are terrorist attacks affecting religion? 
• What are the new ideologies becoming popular?
• How are Hinduism, Buddhism, and Jainism connected?
• Teachings of Hinduism (you can choose any religion)
• What influence do religions have on the perception of right and wrong?
• Can other religions help to change the view of women in Arabic cultures?

Social Media

• Are social media making us lonely, empty from the inside, and unsociable?
• How to protect children online?
• What are some techniques to identify pedophiles on social media?
• Why do people have the want to post everything online?
• How to prevent cyber-bullying?
• Can LinkedIn help people find jobs or further education?
• How to make a break from social media?
• Why are more adolescent generations obsessed with the number of followers and likes?
• How bad is social media addiction?
• Who are world-famous influencers on social media?
• What is causing the rise in popularity of classical music?
• Why are world-famous musicians more prone to become drug abusers?
• History and the rise of hip-hop culture
• Why do people listen to sad music when they do not feel good?
• What happens to your mind when you listen to 432 HZ frequency music?
• How is the US education system different from the education systems in other countries?
• Impact of college debt on the future life choices of students?
• What benefits do physical education classes have on students' health?
• Do children who attend preschool excel in school in the future?
• What are the advantages and disadvantages of the Montessori Method ?
• Do students learn better in same-sex classrooms?
• Do students who get free meals at school get higher grades than those who do not receive any free meal?
• Impact of technology on studies
• What was the impact of the No Child Left Behind act?
• Homeschoolers VS Traditional school; who performs better in the college 

Current Affairs

• How have the motives of feminists changed over the decades?
• What are the impacts of China’s one-child policy?
• What factors gave rise to the current decline in the rate of unemployment?
• Difference between US immigration laws and immigration laws of other countries
• Explain the history of the relationship between the United States and North Korea.
• Explain Brexit
• What factors contributed to China becoming a superpower?
• How has the “Black Lives Matter” movement affected the view about racism in the world?
• How will India become a superpower in 2050?
• History and rise of Bitcoin and another cryptocurrency 

Conclusion 

Make sure to do your research before you start writing. You do not have to make a mistake to start writing your research paper and then learn that there is not enough information to foster your research. 

In some cases, your research can contradict the points you are trying to explain. Get most of your research done before your start writing. Create an outline to understand your flow. This will help keep your paper clear and structured, and you will get clarity to produce a strong report.

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113 Great Research Paper Topics

General Education

One of the hardest parts of writing a research paper can be just finding a good topic to write about. Fortunately we've done the hard work for you and have compiled a list of 113 interesting research paper topics. They've been organized into ten categories and cover a wide range of subjects so you can easily find the best topic for you.

In addition to the list of good research topics, we've included advice on what makes a good research paper topic and how you can use your topic to start writing a great paper.

What Makes a Good Research Paper Topic?

Not all research paper topics are created equal, and you want to make sure you choose a great topic before you start writing. Below are the three most important factors to consider to make sure you choose the best research paper topics.

#1: It's Something You're Interested In

A paper is always easier to write if you're interested in the topic, and you'll be more motivated to do in-depth research and write a paper that really covers the entire subject. Even if a certain research paper topic is getting a lot of buzz right now or other people seem interested in writing about it, don't feel tempted to make it your topic unless you genuinely have some sort of interest in it as well.

#2: There's Enough Information to Write a Paper

Even if you come up with the absolute best research paper topic and you're so excited to write about it, you won't be able to produce a good paper if there isn't enough research about the topic. This can happen for very specific or specialized topics, as well as topics that are too new to have enough research done on them at the moment. Easy research paper topics will always be topics with enough information to write a full-length paper.

Trying to write a research paper on a topic that doesn't have much research on it is incredibly hard, so before you decide on a topic, do a bit of preliminary searching and make sure you'll have all the information you need to write your paper.

#3: It Fits Your Teacher's Guidelines

Don't get so carried away looking at lists of research paper topics that you forget any requirements or restrictions your teacher may have put on research topic ideas. If you're writing a research paper on a health-related topic, deciding to write about the impact of rap on the music scene probably won't be allowed, but there may be some sort of leeway. For example, if you're really interested in current events but your teacher wants you to write a research paper on a history topic, you may be able to choose a topic that fits both categories, like exploring the relationship between the US and North Korea. No matter what, always get your research paper topic approved by your teacher first before you begin writing.

113 Good Research Paper Topics

Below are 113 good research topics to help you get you started on your paper. We've organized them into ten categories to make it easier to find the type of research paper topics you're looking for.

Arts/Culture

• Discuss the main differences in art from the Italian Renaissance and the Northern Renaissance .
• Analyze the impact a famous artist had on the world.
• How is sexism portrayed in different types of media (music, film, video games, etc.)? Has the amount/type of sexism changed over the years?
• How has the music of slaves brought over from Africa shaped modern American music?
• How has rap music evolved in the past decade?
• How has the portrayal of minorities in the media changed?

Current Events

• What have been the impacts of China's one child policy?
• How have the goals of feminists changed over the decades?
• How has the Trump presidency changed international relations?
• Analyze the history of the relationship between the United States and North Korea.
• What factors contributed to the current decline in the rate of unemployment?
• What have been the impacts of states which have increased their minimum wage?
• How do US immigration laws compare to immigration laws of other countries?
• How have the US's immigration laws changed in the past few years/decades?
• How has the Black Lives Matter movement affected discussions and view about racism in the US?
• What impact has the Affordable Care Act had on healthcare in the US?
• What factors contributed to the UK deciding to leave the EU (Brexit)?
• What factors contributed to China becoming an economic power?
• Discuss the history of Bitcoin or other cryptocurrencies  (some of which tokenize the S&P 500 Index on the blockchain) .
• Do students in schools that eliminate grades do better in college and their careers?
• Do students from wealthier backgrounds score higher on standardized tests?
• Do students who receive free meals at school get higher grades compared to when they weren't receiving a free meal?
• Do students who attend charter schools score higher on standardized tests than students in public schools?
• Do students learn better in same-sex classrooms?
• How does giving each student access to an iPad or laptop affect their studies?
• What are the benefits and drawbacks of the Montessori Method ?
• Do children who attend preschool do better in school later on?
• What was the impact of the No Child Left Behind act?
• How does the US education system compare to education systems in other countries?
• What impact does mandatory physical education classes have on students' health?
• Which methods are most effective at reducing bullying in schools?
• Do homeschoolers who attend college do as well as students who attended traditional schools?
• Does offering tenure increase or decrease quality of teaching?
• How does college debt affect future life choices of students?
• Should graduate students be able to form unions?

• What are different ways to lower gun-related deaths in the US?
• How and why have divorce rates changed over time?
• Is affirmative action still necessary in education and/or the workplace?
• Should physician-assisted suicide be legal?
• How has stem cell research impacted the medical field?
• How can human trafficking be reduced in the United States/world?
• Should people be able to donate organs in exchange for money?
• Which types of juvenile punishment have proven most effective at preventing future crimes?
• Has the increase in US airport security made passengers safer?
• Analyze the immigration policies of certain countries and how they are similar and different from one another.
• Several states have legalized recreational marijuana. What positive and negative impacts have they experienced as a result?
• Do tariffs increase the number of domestic jobs?
• Which prison reforms have proven most effective?
• Should governments be able to censor certain information on the internet?
• Which methods/programs have been most effective at reducing teen pregnancy?
• What are the benefits and drawbacks of the Keto diet?
• How effective are different exercise regimes for losing weight and maintaining weight loss?
• How do the healthcare plans of various countries differ from each other?
• What are the most effective ways to treat depression ?
• What are the pros and cons of genetically modified foods?
• Which methods are most effective for improving memory?
• What can be done to lower healthcare costs in the US?
• What factors contributed to the current opioid crisis?
• Analyze the history and impact of the HIV/AIDS epidemic .
• Are low-carbohydrate or low-fat diets more effective for weight loss?
• How much exercise should the average adult be getting each week?
• Which methods are most effective to get parents to vaccinate their children?
• What are the pros and cons of clean needle programs?
• How does stress affect the body?
• Discuss the history of the conflict between Israel and the Palestinians.
• What were the causes and effects of the Salem Witch Trials?
• Who was responsible for the Iran-Contra situation?
• How has New Orleans and the government's response to natural disasters changed since Hurricane Katrina?
• What events led to the fall of the Roman Empire?
• What were the impacts of British rule in India ?
• Was the atomic bombing of Hiroshima and Nagasaki necessary?
• What were the successes and failures of the women's suffrage movement in the United States?
• What were the causes of the Civil War?
• How did Abraham Lincoln's assassination impact the country and reconstruction after the Civil War?
• Which factors contributed to the colonies winning the American Revolution?
• What caused Hitler's rise to power?
• Discuss how a specific invention impacted history.
• What led to Cleopatra's fall as ruler of Egypt?
• How has Japan changed and evolved over the centuries?
• What were the causes of the Rwandan genocide ?

• Why did Martin Luther decide to split with the Catholic Church?
• Analyze the history and impact of a well-known cult (Jonestown, Manson family, etc.)
• How did the sexual abuse scandal impact how people view the Catholic Church?
• How has the Catholic church's power changed over the past decades/centuries?
• What are the causes behind the rise in atheism/ agnosticism in the United States?
• What were the influences in Siddhartha's life resulted in him becoming the Buddha?
• How has media portrayal of Islam/Muslims changed since September 11th?

Science/Environment

• How has the earth's climate changed in the past few decades?
• How has the use and elimination of DDT affected bird populations in the US?
• Analyze how the number and severity of natural disasters have increased in the past few decades.
• Analyze deforestation rates in a certain area or globally over a period of time.
• How have past oil spills changed regulations and cleanup methods?
• How has the Flint water crisis changed water regulation safety?
• What are the pros and cons of fracking?
• What impact has the Paris Climate Agreement had so far?
• What have NASA's biggest successes and failures been?
• How can we improve access to clean water around the world?
• Does ecotourism actually have a positive impact on the environment?
• Should the US rely on nuclear energy more?
• What can be done to save amphibian species currently at risk of extinction?
• What impact has climate change had on coral reefs?
• How are black holes created?
• Are teens who spend more time on social media more likely to suffer anxiety and/or depression?
• How will the loss of net neutrality affect internet users?
• Analyze the history and progress of self-driving vehicles.
• How has the use of drones changed surveillance and warfare methods?
• Has social media made people more or less connected?
• What progress has currently been made with artificial intelligence ?
• Do smartphones increase or decrease workplace productivity?
• What are the most effective ways to use technology in the classroom?
• How is Google search affecting our intelligence?
• When is the best age for a child to begin owning a smartphone?
• Has frequent texting reduced teen literacy rates?

How to Write a Great Research Paper

Even great research paper topics won't give you a great research paper if you don't hone your topic before and during the writing process. Follow these three tips to turn good research paper topics into great papers.

#1: Figure Out Your Thesis Early

Before you start writing a single word of your paper, you first need to know what your thesis will be. Your thesis is a statement that explains what you intend to prove/show in your paper. Every sentence in your research paper will relate back to your thesis, so you don't want to start writing without it!

As some examples, if you're writing a research paper on if students learn better in same-sex classrooms, your thesis might be "Research has shown that elementary-age students in same-sex classrooms score higher on standardized tests and report feeling more comfortable in the classroom."

If you're writing a paper on the causes of the Civil War, your thesis might be "While the dispute between the North and South over slavery is the most well-known cause of the Civil War, other key causes include differences in the economies of the North and South, states' rights, and territorial expansion."

#2: Back Every Statement Up With Research

Remember, this is a research paper you're writing, so you'll need to use lots of research to make your points. Every statement you give must be backed up with research, properly cited the way your teacher requested. You're allowed to include opinions of your own, but they must also be supported by the research you give.

#3: Do Your Research Before You Begin Writing

You don't want to start writing your research paper and then learn that there isn't enough research to back up the points you're making, or, even worse, that the research contradicts the points you're trying to make!

Get most of your research on your good research topics done before you begin writing. Then use the research you've collected to create a rough outline of what your paper will cover and the key points you're going to make. This will help keep your paper clear and organized, and it'll ensure you have enough research to produce a strong paper.

What's Next?

Are you also learning about dynamic equilibrium in your science class? We break this sometimes tricky concept down so it's easy to understand in our complete guide to dynamic equilibrium .

Thinking about becoming a nurse practitioner? Nurse practitioners have one of the fastest growing careers in the country, and we have all the information you need to know about what to expect from nurse practitioner school .

Want to know the fastest and easiest ways to convert between Fahrenheit and Celsius? We've got you covered! Check out our guide to the best ways to convert Celsius to Fahrenheit (or vice versa).

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Update on Hypertension Research in 2021

Masaki mogi.

1 Department of Pharmacology, Ehime University Graduate School of Medicine, 454 Shitsukawa, Tohon, Ehime 791-0295 Japan

Tatsuya Maruhashi

2 Department of Regenerative Medicine, Division of Radiation Medical Science, Research Institute for Radiation Biology and Medicine, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8553 Japan

Yukihito Higashi

3 Division of Regeneration and Medicine, Medical Center for Translational and Clinical Research, Hiroshima University Hospital, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551 Japan

Takahiro Masuda

4 Division of Nephrology, Department of Medicine, Jichi Medical University School of Medicine, 3311-1, Yakushiji, Shimotsuke, Tochigi 329-0498 Japan

Daisuke Nagata

Michiaki nagai.

5 Department of Cardiology, Hiroshima City Asa Hospital, 1-2-1 Kameyamaminami Asakita-ku, Hiroshima, 731-0293 Japan

Kanako Bokuda

6 Department of Endocrinology and Hypertension, Tokyo Women’s Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666 Japan

Atsuhiro Ichihara

Yoichi nozato.

7 Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, 2-2, Yamada-oka, Suita, Osaka 565-0871 Japan

8 Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, Sakaecho, Itabashi-ku, Tokyo 173-0015 Japan

Keisuke Narita

9 Division of Cardiovascular Medicine, Department of Medicine, Jichi Medical University School of Medicine, 3311-1, Yakushiji, Shimotsuke, Tochigi 329-0498 Japan

Satoshi Hoshide

Atsushi tanaka.

10 Department of Cardiovascular Medicine, Saga University, 5-1-1, Nabeshima, Saga, 849-8501 Japan

Koichi Node

Yuichi yoshida.

11 Department of Endocrinology, Metabolism, Rheumatology and Nephrology, Faculty of Medicine, Oita University, 1-1, 1-1 Idaigaoka, Hasama-machi, Yufu city, Oita 879-5593 Japan

Hirotaka Shibata

Kenichi katsurada.

12 Division of Clinical Pharmacology, Department of Pharmacology, Jichi Medical University School of Medicine, 3311-1, Yakushiji, Shimotsuke, Tochigi 329-0498 Japan

Masanari Kuwabara

13 Department of Cardiology, Toranomon Hospital, 2-2-2, Toranomon, Minato-ku, Tokyo 105-8470 Japan

Takahide Kodama

Keisuke shinohara.

14 Department of Cardiovascular Medicine, Faculty of Medical Sciences, Kyushu University, 3-1-1, Maidashi, Higashi-ku, Fukuoka, 812-8582 Japan

Kazuomi Kario

Associated data.

In 2021, 217 excellent manuscripts were published in Hypertension Research. Editorial teams greatly appreciate the authors’ contribution to hypertension research progress. Here, our editorial members have summarized twelve topics from published work and discussed current topics in depth. We hope you enjoy our special feature, “Update on Hypertension Research in 2021”.

Usefulness of vascular function tests for cardiovascular risk assessment and a better understanding of the pathophysiology of atherosclerosis in hypertension (see Supplementary Information  1 )

Vascular function tests and vascular imaging tests are useful for assessing the severity of atherosclerosis. Since vascular dysfunction and vascular morphological alterations are closely associated with the maintenance and progression of atherosclerosis, vascular tests may provide additional information for cardiovascular risk assessment (Fig.  1 ) [ 1 – 5 ]. Measurement of the ankle-brachial index (ABI) has been performed not only for screening for peripheral artery disease but also for cardiovascular risk assessment in clinical practice [ 6 ]. However, the ABI method does not always provide reliable data because the ABI value is falsely elevated despite the presence of occlusive arterial lesions in the lower extremities of patients with noncompressible lower limb arteries, which can lead to incorrect cardiovascular risk assessment [ 7 – 9 ]. Tsai et al. [ 10 ] reported that a combination of an ABI value <0.9 and an interleg ABI difference ≥0.17 was more useful for predicting all-cause mortality and cardiovascular mortality than was an ABI value <0.9 alone. Therefore, attention should be given not only to the ABI value but also to the interleg ABI difference for more precise cardiovascular risk assessment. Sang et al. [ 11 ] conducted a systematic review and meta-analysis to investigate the usefulness of brachial-ankle pulse wave velocity (baPWV), an index of arterial stiffness, for risk assessment and showed that higher baPWV was significantly associated with a higher risk of cardiovascular events, cardiovascular mortality, and all-cause mortality in patients with a history of coronary artery disease or stroke.

Vascular function tests and vascular imaging tests for the assessment of cardiovascular risk. CV cardiovascular

Vascular tests are also useful to achieve a better understanding of the underlying pathophysiology of cardiac disorders. Harada et al. [ 12 ] reported that short stature defined as height <155.0 cm was associated with low flow-mediated vasodilation (FMD), an index of endothelial function, in Japanese men, supporting the association between short stature and high risk of cardiovascular events [ 13 ]. Cassano et al. [Supplementary Information  1 - 1 ] reported that low levels of endothelial progenitor cells (EPCs) at baseline were associated with impaired endothelial function assessed by the reactive hyperemia index (RHI) and impaired arterial stiffness assessed by carotid-femoral PWV (cfPWV) at baseline and that EPC levels at baseline were also associated with longitudinal changes in RHI and cfPWV three years after the initiation of antihypertensive drug treatment in patients with hypertension. Murai et al. [Supplementary Information  1 - 2 ]. reported that a higher area under the curve value of insulin during a 75-g oral glucose tolerance test, but not insulin sensitivity indices, was significantly associated with higher baPWV in young Japanese subjects aged <40 years. Miyaoka et al. [ 14 ] reported that baPWV and central systolic blood pressure were significantly associated with renal microvascular damage assessed by using renal biopsy specimens in patients with nondiabetic kidney disease. Vila et al. [Supplementary Information  1 - 3 ] reported that carotid intima-media thickness (IMT) was significantly greater in male patients with autoimmune disease than in age-matched male controls without autoimmune disease, supporting a role for immune-mediated inflammation in the pathogenesis of atherosclerosis. Li et al. [Supplementary Information  1 - 4 ] showed in a cross-sectional study that increased carotid IMT was significantly associated with cognitive impairment assessed by the Mini-Mental State Examination in Chinese patients with hypertension, especially patients who were ≥60 years of age and patients with low high-density lipoprotein cholesterol levels (<40 mg/dL).

Vascular function is profoundly affected by habitual behavior. Fryer et al. [Supplementary Information  1 - 5 ] reported that central arterial stiffness and peripheral arterial stiffness assessed by cfPWV and PWV β were more deteriorated by uninterrupted prolonged sitting (180 min) combined with prior high-fat meal consumption (61 g fat, 1066 kcal) than by uninterrupted prolonged sitting combined with prior low-fat meal consumption (10 g fat, 601 kcal) in healthy nonsmoking male subjects, suggesting that high-fat meal consumption should be avoided before uninterrupted prolonged sitting to prevent the progression of arterial stiffening. Yamaji et al. [ 15 ] reported that endothelial function assessed by FMD and vascular smooth muscle function assessed by nitroglycerine-induced vasodilation of the brachial artery were more impaired in patients without daily stair climbing activity than in patients who habitually climbed stairs to the ≥3 rd floor among patients with hypertension. Funakoshi et al. [ 16 ] reported that eating within 2 h before bedtime ≥3 days/week was associated with the development of hypertension defined as blood pressure ≥140/90 mmHg or initiation of antihypertensive drug treatment during an average follow-up period of 4.5 years in the general Japanese population, suggesting that avoiding late dinners may be helpful for preventing the development of hypertension. These findings indicate the importance of lifestyle modifications for maintaining vascular function and preventing the development of hypertension and the progression of atherosclerosis.

(TM and YH)

Keywords : vascular function, endothelial function, arterial stiffness, carotid intimathickness, ankle-brachial index.

Advances in hypertension management for better renal outcomes (See Supplementary Information 2 )

In chronic kidney disease (CKD) patients, hypertension is a risk factor for end-stage renal disease (ESRD), cardiovascular events and mortality. Thus, the prevention and appropriate management of hypertension in CKD patients are important strategies for preventing ESRD and cardiovascular disease (Fig.  2 ).

Advantages of hypertension in CKD. CKD chronic kidney disease, GFR glomerular filtration rate, MR mineralocorticoid receptor, SGLT2 sodium–glucose cotransporter 2

Risk factors for hypertension

Fibroblast growth factor 21 (FGF21) is an endocrine hormone that is mainly secreted by the liver. Circulating FGF21 levels are reported to be increased in CKD patients, while higher circulating FGF21 levels were reported to be associated with all-cause mortality in ESRD patients [ 17 , 18 ]. Additionally, Matsui et al. reported that higher circulating FGF21 levels partially mediate the association of elevated BP and/or aortic stiffness with renal dysfunction in middle-aged and older adults [ 19 ]. A study by Funakoshi et al. showed that eating before bed was correlated with the future risk of developing hypertension in the Iki Epidemiological Study of Atherosclerosis and Chronic Kidney Disease [Supplementary Information  2 - 1 ].

Prognostic markers

Several promising prognostic markers for renal and cardiovascular outcomes have been suggested. Matsukuma et al. reported that a higher urinary sodium-to-potassium ratio was independently associated with poor renal outcomes in patients with CKD [Supplementary Information  2 - 2 ]. Chinese hypertensive patients with higher albumin-to-creatinine ratios had a significantly increased risk of first ischemic stroke [Supplementary Information  2 - 3 ]. The number of nephrons in hypertensive patients was significantly lower than that in controls [ 20 ]. Tsuboi et al. suggested the usefulness of methods to estimate the total nephron count and single nephron GFR in living patients, which helped to tailor patient care depending on age or disease stage as well as to predict the response to therapy and the disease outcome [ 21 ].

Mineralocorticoid receptor (MR) blockers (e.g., esaxerenone) are used in the treatment of essential hypertension and hyperaldosteronism. Recently, a new MR antagonist, finerenone, has been introduced as a treatment for CKD patients with type 2 diabetes. However, hyperkalemia has been recognized as a potential side effect during treatment with MR blockers. A recent review article by Rakugi et al. suggested that being aware of at-risk patient groups, choosing appropriate dosages, and monitoring serum potassium during therapy are required to ensure the safe clinical use of these agents [Supplementary Information  2 - 4 ].

The clinical use of sodium–glucose cotransporter-2 inhibitors (SGLT2is) has recently been expanded to nondiabetic patients with CKD and heart failure as well as diabetic patients [ 22 , 23 ]. Several novel findings regarding the renal protective properties of SGTL2is were reported in 2021. In a real-world registry study of Japanese type 2 diabetes patients with CKD, SGLT2is were associated with significantly better kidney outcomes in comparison to other glucose-lowering drugs, irrespective of the presence or absence of proteinuria [ 24 ]. Kitamura et al. reported that the addition of metformin to SGLT2is blunts the decrease in eGFR but that the coadministration of RAS inhibitors ameliorates this response [Supplementary Information  2 - 5 ]. Thomson and Vallon reported that (1) SGLT2i treatment reduces glomerular capillary pressure that is mediated through tubuloglomerular feedback (TGF) and (2) the TGF response to SGLT2is involves preglomerular vasoconstriction and postglomerular vasorelaxation [ 25 ].

SGLT2is have an antihypertensive effect, which is greater in subjects with higher salt sensitivity and BMI [ 26 – 28 ]. Furthermore, the degree of BP change in patients undergoing SGLT2i therapy depends on the baseline BP; a larger reduction is observed in patients with higher baseline BP, and a smaller reduction or slight increase is observed in patients with lower baseline BP [ 29 ]. These BP regulation mechanisms may partially depend on body fluid homeostasis by SGLT2is. SGLT2is ameliorate fluid retention through osmotic diuresis and natriuresis but are associated with a low rate of hypovolemia [ 30 – 33 ], which is evident by the compensatory upregulation of renin and vasopressin levels [ 33 – 35 ]. These fluid homeostatic mechanisms exerted by SGLT2is may contribute to the stabilization of BP. Moreover, recent clinical studies have shown that SGLT2is reduce BP without changes in urinary sodium and fluid excretion or plasma volume [ 35 – 37 ], suggesting the role of other factors, such as the inhibition of the sympathetic nervous system, restoration of endothelial function, and reduction of arterial stiffness [ 38 , 39 ].

(TM and DN)

Keywords : fibroblast growth factor 21, nephron number, mineralocorticoid receptor blocker, SGLT2 inhibitor, fluid homeostasis.

Hypertension and heart disease-focusing on the relationship with HFpEF (See Supplementary Information 3 )

With the increasing longevity of ‘Westernized’ populations, heart failure (HF) in the elderly has become a problem of growing scale and complexity worldwide [ 40 ].

Stages of HF are classified from A to D [ 41 ]. HF patients are also divided into patients with preserved ejection fraction (EF) (HFpEF), those with mildly reduced EF and those with reduced EF (HFrEF). Persistent hypertension and increased arterial stiffness in stage A HF result in left ventricular (LV) hypertrophy (LVH), at which point it is classified as stage B HF. Although the etiology of HFpEF is diverse, patients with HFpEF have been reported to have a high prevalence of hypertension, which is closely associated with increased arterial stiffness, LVH and diastolic LV dysfunction [ 41 ].

In adult Sprague–Dawley rats, a novel flavoprotein, renalase, was increased in hypertrophic cardiac tissue, and recombinant renalase improved cardiac function and suppressed myocardial fibrosis in the HF model [ 42 ]. In stroke-prone spontaneously hypertensive rats, carboxypeptidase X 2 (Cpxm2) was identified as a locus that affects LV mass. Analysis of endomyocardial biopsies from LVH patients showed significant upregulation of CPXM2 expression [ 43 ]. In this way, basic research applied to humans has shown in detail the pathophysiology of LVH.

Left atrial (LA) enlargement (LAe) is also associated with HFpEF [ 44 ]. In response to proinflammatory mediators, microvascular endothelial cells become inappropriately activated, resulting in microvascular endothelial dysfunction, perpetuating the inflammatory process and LA fibrosis [ 45 ]. Manifestations of these mechanisms have been related to LAe, which can be detected prior to the incidence of atrial fibrillation. Sympathetic overdrive from the central autonomic network, including the insular cortex, causes LA-pulmonary vein (PV) border fibrosis. LA-PV border fibrosis was suggested to originate from local inflammation triggered by preganglionic fibers ending in ganglionated plexi [ 45 , 46 ].

In the SPRINT study, intensive BP management was not associated with LA abnormalities defined based on ECG [ 47 ]. Although LA volume (LAV) according to body surface area was recommended to assess LA size [ 48 ], LAV indexed for height 2 was shown to be more sensitive for detecting subclinical hypertensive organ damage in females [ 49 ]. In the ARIC study, the minimum but not the maximum LAV index was significantly associated with the risk of incident HFpEF or death [ 50 ].

In the 2021 European Society of Cardiology guidelines for the treatment of HFrEF, angiotensin receptor/neprilysin inhibitor (ARNI) and sodium–glucose cotransporter 2 inhibitor (SGLT2i) are newly recommended for first-line treatment. In contrast, no guideline-directed treatment has been shown to convincingly reduce mortality and morbidity in HFpEF patients [ 44 ].

BP control is important to prevent adverse events in HFpEF patients with high BP. In a randomized study of hypertension patients, a significant reduction in systolic blood pressure (BP) (SBP) and diastolic BP was observed during daytime and nighttime in the ARNI group compared to the placebo group [ 51 ]. ARNI was also associated with reduced BP in patients with refractory hypertension with HFpEF [ 52 ]. In the PARAGON-HF trial, a decrease in pulse pressure, a marker of large arterial stiffness, during ARNI run-in was associated with a significant improvement in the prognosis of HFpEF [ 53 ]. On the other hand, the SACRA study showed that a significant reduction in BP occurred after adding SGLT2i to existing antihypertensive and antidiabetic agents in nonsevere obese diabetic elderly with uncontrolled nocturnal hypertension [ 54 ]. Recently, in the EMPEROR-Preserved Trial, SGLT2i improved the prognosis of patients with HFpEF [ 55 ]. From the above, it is suggested that reducing nighttime BP and improving diurnal BP patterns improves the prognosis of HFpEF [ 56 , 57 ].

Accumulated evidence from basic and clinical studies suggests that hypertension is a crucial risk factor for HFpEF (Fig.  3 ). These data may contribute to future studies aimed at elucidating the more detailed pathophysiology of HFpEF in hypertension research and the development of therapeutic agents and/or strategies that improve the prognosis of HFpEF in hypertension.

A scheme of the relationship between hypertension and HFpEF. The dysregulation of the central autonomic network is associated with enhanced sympathetic nervous system activity in hypertension linked to HFpEF via left atrial remodeling, left ventricular hypertrophy and increased arterial stiffness. HFpEF heart failure with preserved ejection fraction, LA left atrium, PV pulmonary vein

Keywords : heart failure with preserved ejection fraction, arterial stiffness, leftventricular hypertrophy, diastolic left ventricular dysfunction, left atrial remodeling.

Up-to-date preeclampsia knowledge; what we should know for mother and child (See Supplementary Information 4 )

Diagnostic criterion.

In 2017, the American College of Cardiology/American Heart Association hypertension treatment guidelines identified hypertension as blood pressure (BP) ≥ 130/80 mmHg. The reference BP for hypertension during pregnancy as specified in international guidelines [e.g., the International Society for the Study of Hypertension in Pregnancy guidelines (ISSHP) [ 58 ] and the American College of Obstetricians and Gynecologists guidelines (ACOG) [ 59 , 60 ]] is ≥140/90 mmHg. A large number of studies have examined the incidence of PE and fetal outcomes according to BP levels. The meta-analysis of these studies has shown that BP ≥ 120/80 mmHg, particularly ≥130/80 mmHg, in early pregnancy is also associated with increased maternal and perinatal risks and proposed new BP categories of <120/80 mmHg (normal), 120–129/<80 mmHg (high normal), and 130–139/80–89 mmHg (elevated) for pregnant women [ 61 ].

Prognostic tools

The predictive value of BP and other clinical characteristics for PE is relatively low [ 62 , 63 ]. Soluble fms-like tyrosine kinase 1 (sFlt-1)/placental growth factor (PlGF) ratio testing resulted in reduced unnecessary hospitalization [ 64 , 65 ]. Circulating cell-free DNA (cfDNA) and human suppression of tumorigenesis 2 (ST2) were increased in individual with gestational hypertension (GH) and PE and served as diagnostic biomarkers [Supplementary Information  4 - 1 ]. Nocturnal hypertension was a significant predictor of early-onset PE in high-risk pregnancies [ 66 ]. BP variability was higher in pregnant women with hypertensive disorders and was significantly associated with left ventricular mechanics [Supplementary Information  4 - 2 ]. Including these factors in multivariate models may improve the detection rates of PE and may identify women who could benefit from preventive interventions (Fig.  4 ).

Schematic presentation of the topics of preeclampsia 2021. HTN hypertension, PE preeclampsia, BP blood pressure, cfDNA cell-free DNA, ST2 human suppression of tumorigenesis 2, sFlt-1 soluble fms-like tyrosine kinase-1, PIGF placental growth factor, PRES posterior reversible encephalopathy syndrome, AKI acute kidney injury, ACE angiotensinogen converting enzyme, Ang angiotensin

The ISSHP recommends that BP ≥ 140/90 mmHg should be treated, with a goal BP of 110–140/85 mmHg, while the ACOG recommends antihypertensive medications when BP ≥ 160/110 mmHg, with goal BP below this threshold (Fig.  4 ). Systolic BP (sBP) < 130 mmHg within 14 weeks of gestation reduced the risk of developing early-onset superimposed PE in women with chronic hypertension [ 67 ]. The Chronic Hypertension and Pregnancy (CHAP) project also showed that BP control to <140/90 was associated with a reduction in composite adverse outcomes, with no significant increase in small for gestational age infants [ 68 ].

Long-term outcomes

PE is linked to major chronic diseases such as hypertension, type 2 diabetes mellitus, dyslipidemia, and cardiovascular disease (Fig.  4 ). The American Heart Association lists hypertension during pregnancy as a major cardiovascular risk factor and recommends that affected women undergo cardiovascular risk screening within 3 months after giving birth [ 69 ]. Since many cardiovascular risk factors are modifiable and related to lifestyle, all women with prior PE should be followed up by physicians even after the resolution of PE.

COVID-19 and Pregnancy

Pregnancy could potentially affect the susceptibility to and severity of COVID-19. Severe cases of COVID-19 present with PE-like symptoms. PE mimicry by COVID-19 was confirmed following the alleviation of preeclamptic symptoms without delivery of the placenta [ 70 ]. In COVID-19, angiotensin-converting enzyme 2 (ACE 2) function decreases, and subsequently, angiotensin II (Ang) activity increases [ 71 ]. Similar to PE, COVID-19 results in an increase in the sFlt-1/PlGF ratio due to pathologic Ang II/Ang (1-7) imbalance [ 72 ] (Fig.  4 ). Most experts believe that SARS-CoV-2 is likely to become endemic, and continued collection of data on the effects of COVID-19 during pregnancy is needed.

Further investigation is needed to decrease PE-related maternal and fetal deaths and to reduce maternal risks for chronic diseases in later life. The participation of physicians is necessary to offer appropriate medical care to women with prior PE, and continued publications of issues regarding PE in Hypertension Research are expected.

(KB and AI)

Keywords : preeclampsia, gestational hypertension, chronic hypertension, soluble fms-like tyrosine kinase 1, placental growth factor.

Appropriate blood pressure assessment methods for the prevention of hypertension complications (See Supplementary Information 5 )

Blood pressure (BP) values can vary and fluctuate widely depending on the method and the environment of blood measurement. Via appropriate measurement and interpretation of BP values, hypertension can be correctly diagnosed, treated and guided [ 73 ]. To give an example, appropriate body posture is important for accurate BP measurement. Wan et al. [Supplementary Information  5 - 1 ] demonstrated that BP levels measured with the back in an unsupported position were 2.3/1.0 mmHg higher than those measured with the back in a supported position. Glenning et al. [Supplementary Information  5 - 2 ] demonstrated the feasibility of measuring diastolic blood pressure by the onset of the fourth Korotkoff phase (K4), when K5 is undetectable under exercise conditions in children and adolescents. In recent years, a variety of BP measurement devices and techniques have appeared, and accumulating evidence has shown the feasibility, reproducibility, and usefulness of these devices [ 74 , 75 ]. Kario et al. [ 76 ] demonstrated the relationship between BP by a newly released wrist-cuff oscillometric wearable BP device and left ventricular hypertrophy. They concluded the feasibility and usefulness of wearable BP devices to detect masked daytime hypertension. Automated office blood pressure (AOBP) measurement includes recording of several BP readings using a fully automated oscillometric sphygmomanometer with the patient resting alone in a quiet place, thereby potentially minimizing the white-coat effect. The most comprehensive meta-analysis [ 77 ] reported that AOBP is equivalent to home BP (HBP), but the diagnostic value and viability of AOBP are still controversial. Lee et al. [ 78 ] assessed the diagnostic accuracies of two AOBP machines and manual office blood pressure measurements (MOBP) in Chinese individuals and clarified the lower diagnostic significance of AOBP than that of MOBP. Recent studies strongly recommended the wide use of self-measured HBP [ 79 ] because HBP has better reproducibility than office BP (OBP), improves adherence to treatment, enables us to detect high-risk populations and has prognostic value for cardiovascular disease (CVD) events [ 80 – 82 ]. Both elevated morning and nocturnal BP values and disrupted circadian BP rhythm assessed by each BP measurement method or devices are associated with worsened cardiovascular outcomes (Fig.  5 ). Zhan et al. [ 83 ] demonstrated that HBP monitoring improved treatment adherence and BP control in stage 2 and 3 hypertension. Hoshide et al. [ 84 ] demonstrated the association of nighttime BP assessed by HBP and CVD events, independent of N-terminal pro-brain natriuretic peptide (NT-proBNP) levels, in the Japanese clinical population. Narita et al. [Supplementary Information  5 - 3 ] demonstrated that the elevated difference between morning and evening systolic BP was associated with a higher incidence of CVD events in the J-HOP study. Narita et al. [Supplementary Information  5 - 4 ] also demonstrated that treatment-resistant hypertension diagnosed by HBP monitoring was associated with increased CVD risk independent of cardiovascular damage in the same Japanese cohort. Oliveira et al. [Supplementary Information  5 - 5 ] demonstrated that the SAGE score calculated by systolic BP, age, fasting blood glucose and estimated glomerular filtration rate was associated with pulse wave velocity measured by oscillometric devices and concluded that a SAGE score ≥8 could be used to identify a high risk of CVD events. ABPM is currently regarded as the reference method for hypertension diagnosis in children and pregnancy. Salazar et al. [Supplementary Information  5 - 6 ] demonstrated nocturnal hypertension assessed by ABPM as a significant predictor of early-onset preeclampsia/eclampsia in high-risk pregnant women in a cohort study in Argentina. ABPM also helped us to notice abnormal circadian patterns in BP, which are associated with increased circulating volume, largely determined by salt sensitivity and salt intake. Understanding these pathogenic mechanisms under conditions of nocturnal hypertension and heart failure suggests several new antihypertensive pharmacotherapies, including sodium–glucose cotransporter 2 inhibitors, angiotensin receptor neprilysin inhibitors and mineralocorticoid receptor antagonists [ 56 , 85 , 86 ]. Kario et al. [Supplementary Information  5 - 7 ] demonstrated the effect of esaxerenone, a highly selective mineralocorticoid receptor blocker, for improving nocturnal hypertension and NT-proBNP levels. Esaxerenon could be an effective treatment option, especially for nocturnal hypertensive patients with a riser pattern.

Methods of measuring variable blood pressure and evaluating factors associated with the prognosis of cardiovascular disease

Keywords : hypertension management, BP measurement devices, BP variability, home BP, cardiovascular disease

Considering frailty and exercise in the management of hypertension and hypertensive organ damage (See Supplementary Information 6 )

Frailty is defined as physiological decline and a state of vulnerability to stress and results in adverse health outcomes [ 87 ]. Frailty consists of multiple domains, such as physical, social, and psychological factors. Cognitive decline is one of the factors related to frailty, and blood pressure (BP) control significantly reduced dementia or cognitive decline in a meta-analysis [ 88 ]. However, in the elderly population above 80 years, the positive effect of antihypertensive therapy for preventing dementia was not proven [ 89 – 91 ].

A systematic review and meta-analysis of the prevalence of mild cognitive impairment (MCI) among hypertensive patients was conducted by Quin et al. The prevalence of MCI was 30% in a sample of 47,179 hypertensive patients. Heterogeneity was seen due to ethnicity, study design (cross-sectional or cohort study), and cognition assessment tools [ 92 ]. Li. et al. investigated the association between carotid intima thickness (CIMT) and cognitive function in hypertensive patients [Supplementary Information  6 - 1 ]. CIMT was significantly and negatively associated with MMSE scores in people aged ≥60 years but not in those aged <60 years.

BP guidelines in various countries suggest that BP management should be carried out in the context of frailty or end of life, and careful observation, including personalized BP control among elderly individuals, is essential (Fig.  6 ). A total of 535 patients with hypertension (age 78 [ 70 – 84 ] years, 51% men, 37% with frailty) were prospectively followed for 41 months, and mortality associated with frailty and BP was evaluated by Inoue et al. [ 93 ]. Frailty was assessed by the Kihon checklist. Among 49 patients who died, mortality rates were lowest in those with systolic BP < 140 mmHg and nonfrailty and highest in those with systolic BP < 140 mmHg and frailty. The results indicate that frail patients have a higher risk of all-cause mortality than nonfrail patients, and BP should be managed considering frailty status, which is in line with previous reports [ 94 ]. Our latest study showed that in patients with preserved MMSE scores, higher BP was associated with cognitive impairment, and those with MMSE scores below 24 points had the opposite results [ 95 ]. Elderly individuals with hearing impairment have higher rates of hospitalization, mortality, falls, frailty, dementia, and depression. Miyata et al. performed a study using data from medical records from health checkups: higher SBP levels were associated with an increased risk of objective hearing impairment at 1 kHz [Supplementary Information  6 - 2 ].

Hypertension management in frail patients. ADL activities of daily living, IADL instrumental activities of daily living

In the era of technical advancement, people are spending less time being active, which leads to cardiovascular risks, including hypertension. However, guidelines emphasize the importance of nonpharmacological strategies such as lifestyle modification and exercise to prevent diseases [ 96 ].

Sardeli et al. compared types of exercise that are beneficial to health. The study compared the effects of aerobic training (AT), resistance training (RT), and combined training (CT) in hypertensive older adults aged >50 years. There were extensive health benefits associated with exercise training, and CT was the most effective intervention at improving a wide spectrum of health conditions, including cardiorespiratory fitness, muscle strength BMI, fat mass, glucose, TC and TGs [ 97 ]. J Almeida et al. showed that isometric handgrip exercise training reduced systolic BP in treated hypertensive patients [Supplementary Information  6 - 3 ]. Stair climbing and vascular function were assessed by Yamaji et al. There was a significant difference in nitroglycerine-induced vasodilatation between the group with no habits of climbing stairs and the other groups with two or more climbing habits [Supplementary Information  6 - 4 ].

The safety of resistance training was studied by Hansford et al who concluded that isometric resistance training (IRT) was safe and led to a potentially clinically meaningful reduction in BP [Supplementary Information  6 - 5 ].

Keywords : physical and social frailty, elderly, cognitive function, resistance training, cardiorespiratory function

Blood pressure variability—therapeutic target for the prevention of cardiovascular disease (See Supplementary Information 7 )

In the past three decades, there have been many reports on the associations of various parameters of blood pressure (BP) variability with increased risk of cardiovascular disease (CVD) events; these parameters include short-term BP variability (BPV), i.e., beat-by-beat BPV and ambulatory BPV, abnormality of nocturnal BP dipping pattern, and mid- to long-term BPV, i.e., day-by-day BPV, visit-to-visit BPV, and seasonal variations in BP [ 98 – 106 ]. In addition, BPV has been associated with the progression of endovascular organ damage related to heart failure, chronic kidney disease, and cognitive function [ 107 – 111 ] [Supplementary Information  7 - 1 ]. Several factors that are associated with abnormal BPV [ 112 ], as well as environmental factors such as cold or warm temperatures and seasonal changes in climate, increase fluctuations in BP. Individual intrinsic factors, such as sympathetic nervous tone, arterial stiffness, physical activity, and mental stress, also contribute to elevated BPV. According to evaluations of BPV abnormalities, out-of-office BP measurements, such as ambulatory and home BP monitoring, are needed. To evaluate nighttime BP levels, home BP monitoring devices equipped with a function for nighttime BP readings and new wrist-type nocturnal BP monitoring devices are available [ 76 ]. Although there are issues regarding measurement accuracy, cuffless BP monitoring devices, for example, those using pulse transit time, may be used to estimate nighttime BP levels [Supplementary Information  7 - 2 ]. Such cuffless BP devices can also evaluate beat-by-beat BPV. Moreover, by using the multisensor-equipped ambulatory BP monitoring device developed by our research group, it is possible to evaluate BPV associated with changes in temperature, physical activity, and/or atmospheric pressure [ 113 ].

Based on the mechanism(s) underlying a given patient’s BPV abnormality, several methods may be considered for the management of that abnormality (Fig.  7 ). For example, improving excessive sympathetic nervous system activation may be useful in the management of BPV abnormalities [ 114 ], and renal denervation has been reported to decrease ambulatory BPV [ 115 ]. Abnormal nocturnal BP dips may be treated by decreasing nighttime BP. In patients with sleep apnea, improving sleep quality and implementing continuous positive airway pressure are recognized to be useful for nighttime BP control [ 116 ]. Moreover, early adjustment of antihypertensive drugs has been reported to be useful in suppressing seasonal variations in BP, leading to a decreased risk of CVD events [ 99 ]. Furthermore, housing conditions and room temperature are closely related to BP levels, and adaptive control of room temperature would be useful to suppress winter increases in BP [ 117 , 118 ]. In clinical practice, we must not forget that BPV parameters are interrelated. For instance, frequent evaluation of BP levels and adjustment of antihypertensive drugs can suppress visit-to-visit BPV, which in turn leads to the suppression of seasonal variations in BP.

Current and future perspectives in the management of blood pressure variability. Short- and long-term BP variability is associated with CVD event risk independent of each BP level. Out-of-office BP measurements, such as ABPM and home BP monitoring, and other new BP devices are useful for evaluating the various types of BP variability. To suppress BP variability, several management methods, including new antihypertensive medications, chronotherapy, housing condition, and sympathetic nervous denervation, are considered. ABPM ambulatory blood pressure monitoring, ABPV ambulatory blood pressure variability, ARNI angiotensin receptor neprilysin inhibitor, BP blood pressure, BPV blood pressure variability, CVD cardiovascular disease, ICT information and communication technology, SGLT2i sodium–glucose cotransporter 2 inhibitor

Over the next decade, more data on how to manage and control BPV need to be accumulated. Additionally, future studies should be conducted to verify whether the different types of BVP management are useful in preventing CVD events.

(KN, SH and KK)

Keywords : blood pressure variability, out-of-office blood pressure monitoring, cardiovascular disease prevention, wearable blood pressure monitoring device, environmental factors.

Optimal therapy and clinical management of obesity/diabetes (See Supplementary Information 8 )

Obesity/diabetes is a major comorbidity in patients with hypertension, and these conditions often share common pathological conditions, such as insulin resistance and the risk of cardiovascular diseases (CVD). One of the biggest highlights of recent years in the area of obesity/diabetes has been the remarkable benefits of newer glucose-lowering agents seen in large-scale clinical trials on cardiorenal outcomes (Fig.  8 ), followed by the relevant clinical guideline updates and the expansion of the clinical application of those agents [ 119 ]. In particular, sodium–glucose cotransporter 2 inhibitors and glucagon-like peptide-1 receptor agonists are now preferentially recommended in patients with type 2 diabetes (T2D) and specific cardiorenal risk, independent of diabetes status or background use of metformin [ 120 ]. It is noteworthy, of course, that those agents reduced the risk of cardiorenal events, and their multifaceted effects beyond hypoglycemic effects are also attracting clinical attention. In a review series ‘New Horizons in the Treatment of Hypertension’ in Hypertension Research, Tanaka and Node [ 121 ] discussed the modest effects of those agents on blood pressure (BP)-reduction and the clinical perspectives. They also proposed a new-normal style care for diabetes and its complications using such evidence-based agents with multidisciplinary effects, partly aiming at reduced polypharmacy and avoidance of its possible harm. This action will improve the quality of hypertension care in patients with obesity/diabetes; however, a substantial population with treated hypertension still has inadequate blood pressure control, which is recognized as resistant hypertension (RH). Due to the difficulty in distinguishing true RH from pseudo-RH due to nonadherence, little is known about the clinical characteristics of true RH. Chiu et al. from Boston [Supplementary Information  8 - 1 ] reported a notable prevalence (26.6%) of true RH in patients with T2D registered in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Blood Pressure trial and identified several independent predictors, such as higher baseline BP, higher number of baseline antihypertensives, macroalbuminuria, chronic kidney disease, and history of stroke. Moreover, patients with true RH exhibited poorer prognosis than those without, suggesting an emerging need for effective screening and intensified treatment for patients with true RH.

Schematic presentation of the topic ‘Obesity/Diabetes’ in 2021

The BP treatment goal in patients with diabetes and hypertension is less than 130/80 mmHg [ 122 ], and intensified BP control was associated with reduced stroke risk [ 123 – 125 ]. Intensive lipid-lowering therapy is also recommended for patients with T2D at risk of CVD [ 126 ]; however, an original EMPATHY study investigating the effect of intensive lipid-lowering therapy (target of low-density lipoprotein cholesterol [LDL-C] < 70 mg/dL) on cardiovascular outcomes failed to show the clinical benefits of intensive statin therapy in patients with T2D, diabetic retinopathy, elevated LDL-C levels, and no known CVD [ 127 ]. In a subanalysis of the EMPATHY study, Shinohara et al. [ 128 ] revealed for the first time that intensive statin therapy was associated with a reduced risk of cardiovascular events compared with standard therapy (target of ≥100 to <120 mg/dL) in a subgroup with baseline BP ≥ 130/80 mmHg but not in another subgroup with baseline BP < 130/80 mmHg. Their findings suggest that baseline BP is also a possible determinant of the target LDL-C in that patient population, although the precise reasons for the difference in the clinical benefits of intensive statin therapy between subgroups according to baseline BP levels are still uncertain.

Obesity is a crucial global health concern across generations. Obesity and insulin resistance cause several cardiometabolic disorders, including hypertension, and increase the risk of subsequent CVD. Hence, further actions against obesity and cardiometabolic disorders are urgently needed for individuals of all generations [ 129 , 130 ]. In this context, Fernandes et al. from Brazil [Supplementary Information  8 - 2 ] revealed for the first time that Ang-(1-7) and des-Arg9BK metabolites were novel biological markers of adolescent obesity and relevant cardiovascular risk profiles, such as elevated BP, lipids, and inflammation. Thu et al. from Singapore [Supplementary Information  8 - 3 ] found a positive association between accumulated visceral adipose tissue and systolic BP in midlife-aged women, independent of burdens of inflammatory markers. Intriguingly, Haze et al. [ 131 ] clearly demonstrated that an increased ratio of visceral-to subcutaneous fat volume was an independent risk factor for renal dysfunction in Japanese patients with primary aldosteronism. These findings should highlight the clinical importance and the need for further research to explore surrogate markers of obesity in the care of hypertension and its related conditions (Fig.  8 ).

Finally, we briefly introduce some exciting progress in vascular function in the area of “Obesity/Diabetes” (Fig.  8 ). Murai et al. [ 132 ] elegantly showed that postload hyperinsulinemia was independently associated with increased arterial stiffness as assessed by brachial-ankle pulse wave velocity (PWV) in young medical students at Jichi Medical University. Given the close pathological relationship between hyperinsulinemia and most CVDs, including heart failure [ 133 , 134 ], their findings suggest that hyperinsulinemia-induced vascular failure is one of the key drivers of that pathological link. Interestingly, Fryer et al. from the UK [Supplementary Information  8 - 4 ] also found that arterial stiffness as assessed by carotid-femoral PWV was exacerbated by the consumption of a high-fat meal relative to a low-fat meal prior to 180 min of uninterrupted sitting. Importantly, arterial stiffness testing could accurately reflect even such a combination of unfavorable behaviors, and thus vascular function assessment has the potential to reflect a wide spectrum of cardiovascular risk and provide a clinical opportunity for better risk stratification and optimal modification [ 135 ]. We look forward to accumulating and consolidating evidence of vascular function tests and further applying them to actual cardiovascular care [ 136 ].

(AT and KN)

Keywords : glucose-lowering agent, resistant hypertension, statin, surrogate marker, vascular function

A new era of progress in primary aldosteronism treatment: mineralocorticoid receptor antagonists, a new aldosterone assay, and a clinical practice guideline (See Supplementary Information 9 )

A hot topic in 2021 was advances in the treatment of mineralocorticoid receptor (MR)-associated hypertension [ 137 ], particularly primary aldosteronism (PA). The nonsteroidal MR antagonist (MRA) esaxerenone is now widely used in Japan. Kario et al. [ 138 ] reported that esaxerenone reduced nocturnal blood pressure in patients with essential hypertension, according to ambulatory blood pressure assessment and N-terminal pro-brain natriuretic peptide assays. Yoshida et al. [ 139 ] reported that MRAs such as esaxerenone improved quality of life in PA patients. Ito et al. [ 140 ] reported that add-on treatment using esaxerenone with maximal tolerable doses of a renin-angiotensin system (RAS) inhibitor reduced the urinary albumin-creatinine ratio in patients with type 2 diabetes mellitus (ESAX-DN), suggesting a renoprotective effect against diabetic nephropathy. Several clinical studies of another nonsteroidal MRA, finerenone (FIDELIO-DKD [ 141 ], FIGARO-DKD [ 142 ], and FIDELITY [ 143 ]), have shown its renoprotective effect against diabetic nephropathy as well as cardiovascular events, particularly hospitalization for heart failure in patients with type 2 diabetes and chronic kidney disease. Although there are no reports of clinical studies on finerenone for PA, finerenone may be used in the future for type 2 diabetes patients with PA, as obesity, glucose intolerance, and sleep apnea are common complications in patients with PA [ 144 ]. Similarly, sodium–glucose cotransporter 2 inhibitors (SGLT2i) have been demonstrated to improve the prognosis of cardiovascular disease and chronic kidney disease in individuals with type 2 diabetes (EMPA-REG OUTCOME [ 145 ], DECLARE–TIMI 58 [ 146 ], DAPA-HF[ 147 ], and DAPA-CKD [ 22 ]). As steroidal MRAs such as spironolactone and eplerenone are effective in the treatment of mild to severe stages of heart failure (RALES, EPHESUS [ 148 ], and EPHESUS-HF [ 149 ]), combined treatment with MRA and SGLT2i, in addition to an RAS inhibitor, may be a novel effective treatment for cardiac and renal protection in type 2 diabetic patients (Fig.  9 ). Second, radiofrequency ablation of macroscopic adrenal tumors [ 150 – 152 ] has been reported as an alternative treatment for PA to lower blood pressure and plasma aldosterone levels. This treatment has been covered by health insurance providers in Japan since April 2022, but long-term outcomes need to be validated.

Potential drug therapy regimen. Combined administration of an MRA and an SGLT2i may afford cardiac and renal protection. MRA mineralocorticoid receptor antagonist, SGLT2i sodium–glucose cotransporter 2 inhibitor

Another hot topic was the launch of serum aldosterone measurement using a chemiluminescent enzyme immunoassay (CLEIA), which utilizes a two-step sandwich method. Previously, low aldosterone levels may have been measured incorrectly [ 153 ]. The new CLEIA figures are closely correlated with liquid chromatography/tandem mass spectrometry values; the new assay is more accurate than the previous radioimmunoassay, which overestimated serum aldosterone levels [ 154 – 156 ]. Thus, the Japan Endocrine Society issued a Primary Aldosteronism Clinical Guideline in 2021 [ 157 ]. The CLEIA method is also used to measure urinary aldosterone levels; Ozeki et al. [ 158 ] proposed a PA diagnostic cutoff of ≥3 μg/day for the oral salt loading test. The CLEIA method is currently available only in Japan.

Exosomes may serve as biomarkers of MR activity. Ochiai-Homma et al. [ 159 ] focused on pendrin, a Cl – /HCO3 – exchanger that is only expressed by renal intercalated cells. In a rat model, the pendrin level in the urinary exosome was reduced by therapeutic interventions favored for PA patients; the urinary level was correlated with the renal level. This model may help to elucidate the pathophysiology of PA-induced organ injury [ 160 ].

Finally, Haze et al. [Supplementary Information  9 - 1 ], Segawa et al. [Supplementary Information  9 - 2 ], Nishimoto et al. [Supplementary Information  9 - 3 ], Chen et al. [Supplementary Information  9 - 4 ], and Liu et al. [Supplementary Information  9 - 5 ] have conducted intriguing clinical studies regarding PA.

(YY and HS)

Keywords : mineralocorticoid receptor-associated hypertension, mineralocorticoid receptor antagonist, hypertension, primary aldosteronism, chemiluminescent enzyme immunoassay

Advances in renal denervation for treating hypertension: current evidence and future perspectives (See Supplementary Information 10 )

It is well established that renal denervation (RDN) decreases blood pressure (BP) in various models of hypertension in animals and in humans [ 161 – 165 ]. Here, we reviewed studies related to RDN published in Hypertension Research in 2021 (Fig.  10 ). The antihypertensive effect of RDN is mediated by interrupting both the efferent outputs from the brain to the kidney and the afferent inputs from the kidney to the brain, suppressing systemic sympathetic outflow [ 165 , 166 ]. In basic research, there are two methods of RDN: total RDN (TRDN) performed by surgical cutting of renal nerves to ablate both efferent and afferent nerves and selective afferent RDN (ARDN) performed via capsaicin application to renal nerves to specifically ablate afferent nerves expressing capsaicin receptors [ 167 , 168 ]. Katsurada et al. [ 169 ] reviewed previous reports that address the different effects of TRDN and ARDN in different animal models of hypertension, suggesting potentially complicated and diversified origins of hypertension. The potential therapeutic effects of TRDN and ARDN have also been reported in animal models of heart failure [ 170 ].

Topics on renal denervation. BP blood pressure, RDN renal denervation

In clinical practice, radiofrequency, ultrasound, and alcohol-based RDN devices have been developed as second-generation catheter devices and evaluated in randomized control trials. Ogoyama et al. [ 171 ] reported a meta-analysis of nine randomized sham-controlled trials of RDN that showed that RDN significantly reduced a range of office, home and 24 h BP parameters in patients with resistant, uncontrolled, and drug-naïve hypertension. There were no significant differences in the magnitude of BP reduction between radiofrequency-based and ultrasound-based devices.

The Global SYMPLICITY Registry (GSR) is a prospective all-comer registry to evaluate the safety and efficacy of RDN in a real-world population [ 172 ]. The overall GSR has enrolled over 2700 patients, and more than 2300 of these have now been followed for 3 years [ 173 ]. GSR Korea is a Korean registry substudy of GSR ( N  = 102) [ 174 ]. Kim et al. [Supplementary Information  10 - 1 ] reported the 3-year follow-up outcomes from the GSR Korea showing that RDN led to sustained reductions in office systolic BP at 12, 24 and 36 months (−26.7 ± 18.5, −30.1 ± 21.6, and −32.5 ± 18.8 mmHg, respectively) without safety concerns. Recently, the efficacy and safety of second-generation radiofrequency RDN up to 36 months have been reported [ 175 ].

The REQUIRE trial by Kario et al. [Supplementary Information  10 - 2 ] is the first trial of ultrasound RDN in Asian patients from Japan and South Korea with hypertension receiving antihypertensive therapy. The study findings were neutral for the primary endpoint, with similar reductions in 24 h systolic BP at 3 months in the RDN (−6.6 mmHg) and sham control groups (−6.5 mmHg). Although BP reduction after RDN was similar to other sham-controlled studies [ 161 , 162 , 164 , 176 ], the sham group in this study showed much greater reduction. Unlike RADIANCE-HTN TRIO that used an ultrasound catheter system to measure its primary endpoint, REQUIRE did not standardize medications or measure medication adherence, which may lead to increased variability in BP outcome; moreover, REQUIRE was not a double-blind study, which may result in a substantial bias. Another important factor is that 32.4% of patients showed hyperaldosteronism in the REQUIRE trial. Patients with primary aldosteronism have decreased sympathetic nerve activity and are likely to respond poorly to RDN [ 177 ]. The lessons from REQUIRE will enable us to design a follow-up trial to make a definitive evaluation of the effectiveness of RDN in Asian patients with hypertension.

Another topic is the patient preference for RDN. Kario et al. [Supplementary Information  10 - 3 ] conducted a nationwide web-based survey in Japan and reported that preference for RDN was expressed by 755 of 2392 Japanese patients (31.6%) and was higher in males, in younger patients, in those with higher BP, in patients who were less adherent to antihypertensive drug therapy, in those who had antihypertensive drug-related side effects, and in those with comorbid heart failure. This should be taken into account when making shared decisions about antihypertensive therapy.

Keywords : renal nerves, hypertension, renal denervation, patient preference, heart failure

Hot topics in uric acid research: the difficulties of managing hyperuricemia (See Supplementary Information 11 )

The mechanisms linking hyperuricemia, arteriosclerosis, hypertension, chronic kidney disease, and cardiovascular disease are becoming clearer (Fig.  11 ) [ 178 – 181 ]. However, it remains unclear whether treatment of hyperuricemia improves these diseases. Some recent topics of uric acid research are introduced below.

Mechanisms linking hyperuricemia and arteriosclerosis, hypertension, chronic kidney disease, and cardiovascular disease. ATP adenosine triphosphate, CKD chronic kidney disease

First, urate-lowering treatment with allopurinol, a xanthine oxidase (XO) inhibitor, did not slow the decline in eGFR compared with placebo in either the PERL (Preventing Early Renal Loss in Diabetes) trial [ 182 ] or CKD-FIX (Controlled Trial of Slowing of Kidney Disease Progression from the Inhibition of Xanthine Oxidase) [ 183 ]. These results were similar to the results of FEATHER (Febuxostat Versus Placebo Randomized Controlled Trial Regarding Reduced Renal Function in Patients with Hyperuricemia Complicated by Chronic Kidney Disease Stage 3) from Japan [ 184 ]. Moreover, the PRIZE (Program of Vascular Evaluation Under Uric Acid Control by the Xanthine Oxidase Inhibitor Febuxostat: Multicenter, Randomized, Controlled) study showed that febuxostat did not delay the progression of carotid atherosclerosis in patients with asymptomatic hyperuricemia [ 185 ]. These results suggest the difficulties of managing hyperuricemia for preventing chronic kidney disease (CKD) and/or arteriosclerosis.

Second, FAST (the Febuxostat versus Allopurinol Streamlined Trial) showed that febuxostat was noninferior to allopurinol therapy with respect to the primary cardiovascular endpoint, all-cause or cardiovascular deaths [ 186 ]. The results of FAST were different from the results of the CARES (The Cardiovascular Safety of Febuxostat and Allopurinol in Patients with Gout and Cardiovascular Morbidities) trial [ 187 ], and the authors summarized that regulatory advice to avoid the use of febuxostat in patients with cardiovascular disease should be reconsidered and modified [ 186 ].

In Hypertension Research 2021, several important articles on uric acid research were published. Mori et al. reported that a high serum uric acid level is associated with an increase in systolic blood pressure in women but not in men in subjects who underwent annual health checkups [ 188 ]. Their group also reported that a low uric acid level is a significant risk factor for CKD over 10 years in only women, and an elevated UA level increases the risk of CKD in both sexes [Supplementary Information  11 - 1 ]. Moreover, Li et al. reported that elevated serum uric acid levels in subjects without stroke, coronary heart disease, and medication for hyperuricemia or gout aged 40–79 years were independent predictors of total stroke, especially ischemic stroke, in women but not in men in a 10-year cohort study [Supplementary Information  11 - 2 ]. These results suggested the possibility that both hyperuricemia and hypouricemia in women could be associated with a higher risk for hypertension, CKD, and stroke than those in men.

Azegami et al. reported a prediction model of high blood pressure in young adults aged 12–13 years followed up for an average of 8.6 years. The results showed that uric acid was an important predictor of high blood pressure [ 189 ].

Kawasoe et al. reported that high (4.1–5.0, 5.1–6.0, and >/=6.1 mg/dL) and low (</=2.0 mg/dL) serum uric acid levels were significantly associated with an increased prevalence of high blood pressure compared to 2.1–4.0 mg/dL serum uric acid in subjects who underwent health checkups [ 190 ]. The results were compatible with a previous report stratified by sex [ 191 ]. Serum uric acid levels and the risks for diseases are largely different between men and women, and it is desirable to conduct every analysis by sex when conducting uric acid research.

Furuhashi et al. reported that plasma xanthine oxidoreductase (XOR) activity was associated with hypertension in 271 nondiabetic subjects in the Tanno–Sobetsu Study [ 192 ]. Kusunose et al. reported that additional febuxostat treatment in patients with asymptomatic hyperuricemia for 24 months might have potential prevention effects on impaired diastolic dysfunction in the subanalysis of the PRIZE study [ 193 ]. These reports suggested the potential direct antioxidant effects of the treatment as reflected in serum uric acid levels as well as its xanthine-oxidase-lowering properties in tissue [Supplementary Information  11 - 3 ]. Whether the preferential use of xanthine oxidoreductase XO inhibitors becomes a new therapeutic strategy for the prevention of cardiovascular disease in patients with asymptomatic hyperuricemia awaits further high-quality trials [Supplementary Information  11 - 4 ].

Finally, Nishizawa et al. reported a mini review article focusing on the relationship between hyperuricemia and CKD or cardiovascular diseases, and they summarized that high-quality and detailed clinical and basic science studies of hyperuricemia and purine metabolism are needed [Supplementary Information  11 - 5 ].

(MK and TK)

Keywords : uric acid, cardiovascular disease, chronic kidney disease, arteriosclerosis, xanthine oxidase

Basic research: elucidation of the “mosaic” pathogenesis of hypertension (See Supplementary Information 12 )

The pathogenesis of hypertension is multifactorial and highly complex, as described by the “mosaic theory” of hypertension. Basic research plays critical roles in elucidating the “mosaic” pathogenesis of hypertension and developing its treatment (Fig.  12 ).

Topics in basic research. Each ref. number indicates the reference paper cited in the text. AT1R angiotensin type 1 receptor, EV extracellular vesicles, KO knockout, RAS renin-angiotensin system, Snx1 soring nexin 1, SIRT6 sirtuin 6, TWIST1 twist-related protein 1

In the field of the brain and autonomic nervous system, Chen et al. demonstrated that mild cold exposure elicits autonomic dysregulation, such as increased sympathetic activity, decreased baroreflex sensitivity, and poor sleep quality, causing blood pressure (BP) elevation in normotensive rats [ 194 ]. This finding may have critical implications for cardiovascular event occurrence at low ambient temperatures. In addition, Domingos-Souza et al. showed that the ability of baroreflex activation to modulate hemodynamics and induce lasting vascular adaptation is critically dependent on the electrical parameters and duration of carotid sinus stimulation in spontaneously hypertensive rats (SHRs) [ 195 ], proposing a rationale for improving baroreflex activation therapy in humans. Although only normotensive and hypertensive rats were used in these two studies, without comparing the two strains, previous studies have shown that neuronal function and activity in the cardiovascular sympathoregulatory nuclei, including the nucleus tractus solitarius and rostral ventrolateral medulla, which are involved in baroreflex regulation, are different between normotensive and hypertensive rats [ 196 , 197 ]. Further studies comparing normotensive and various hypertensive animal models would be interesting.

In the kidney, Kasacka et al. showed that the activity of the Wnt/β-catenin pathway is increased in SHRs and two-kidney, one-clip (2K1C) hypertensive rats, while it is inhibited in deoxycorticosterone acetate (DOCA)-salt rats according to kidney immunohistochemistry [ 198 ]. The intrarenal renin-angiotensin system (RAS) is also involved in BP regulation. In renal damage with an impaired glomerular filtration barrier, liver-derived angiotensinogen filtered through damaged glomeruli regulates intrarenal RAS activity [ 199 ]. Matsuyama et al. further showed that the glomerular filtration of liver-derived angiotensinogen depending on glomerular capillary pressure causes circadian rhythm of the intrarenal RAS with in vivo imaging using multiphoton microscopy [ 200 ]. Fukuda and his colleagues have shown that complement 3 (C3) is a primary factor that activates intrarenal RAS [Supplementary Information  12 - 1 , 2 ]. Otsuki and Fukuda et al. additionally demonstrated that TWIST1, a transcription factor that regulates mesodermal embryogenesis, transcriptionally upregulates C3 in glomerular mesangial cells from SHRs [ 201 ].

The RAS in the vascular system, as well as in other organ systems, plays a major role in BP regulation. Soring nexins (SNXs) are cellular sorting proteins that can regulate the expression and function of G protein-coupled receptors (GPCRs) [Supplementary Information  12 - 3 , 4 , 5 ]. Liu C et al. demonstrated that SNX1 knockout mice exhibit hypertension through vasoconstriction mediated by increased expression of AT1R, a GPCR mediating most of the effects of angiotensin II (Ang II), within the arteries [ 202 ]. Moreover, in vitro studies suggest that SNX1 sorts arterial AT1R for proteasomal degradation. These findings indicate that SNX1 impairment increases arterial AT1R expression, leading to vasoconstriction and hypertension. Liu X et al. found that sirtuin 6 (SIRT6) expression is downregulated in the aortae of aged rats and showed that SIRT6 knockdown enhances Ang II-induced vascular adventitial aging by activating the NF-κB pathway in vitro [ 203 ]. This study suggests that SIRT6 may be a biomarker of vascular aging and that activating SIRT6 can be a therapeutic strategy for delaying vascular aging.

Several reports indicate the potential treatment for hypertension and the associated organ damage. Narita et al. showed that rivaroxaban exerts a protective effect against cardiac hypertrophy by inhibiting protease-activated receptor-2 signaling in renin-overexpressing hypertensive mice [Supplementary Information  12 - 6 ]. In addition, the efficacy of nebivolol (a third-generation β-blocker), maximakinin (a bradykinin agonist peptide extracted from the skin venom of toad), and Pinggan-Qianyang decoction (a traditional Chinese medicine) were also shown in hypertensive animal models [Supplementary Information  12 - 7 , 8 , 9 ]. In animal models of gestational hypertension, melatonin and crocin have each exhibited an antihypertensive effect [Supplementary Information  12 - 10 , 11 ].

Studies investigating extracellular vesicles (EVs) have increased. Ochiai-Homma et al. showed that pendrin in urinary EVs can be a useful biomarker for the diagnosis and treatment of primary aldosteronism, which was supported by studies using a rat model of aldosterone excess [ 159 ]. Another report indicated that pulmonary arterial hypertension induces the release of circulating EVs with oxidative content and alters redox and mitochondrial homeostasis in the brains of rats [Supplementary Information  12 - 12 ]. Studies on the role of gut microbiota in BP regulation have also been accumulating. Wu et al. demonstrated that captopril has the potential to rebalance the dysbiotic gut microbiota of DOCA-salt hypertensive rats, suggesting that the alteration of the gut flora by captopril may contribute to the hypotensive effect of this drug [ 204 ]. Moreover, important basic studies, including review papers, have been reported in Hypertension Research. See Supplementary Information.

Keywords : autonomic nervous system, kidney, vascular system, renin-angiotensin system, extracellular vesicles, gut microbiota.

Supplementary information

Compliance with ethical standards.

The authors declare no competing interests.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

The online version contains supplementary material available at 10.1038/s41440-022-00967-4.

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Top Recent NLP Research

Featured Post Modeling NLP & LLMs posted by Daniel Gutierrez, ODSC October 1, 2021 Daniel Gutierrez, ODSC

Natural language processing (NLP) including conversational AI is arguably one of the most exciting technology fields today. NLP is important because it works to resolve ambiguity in language and adds useful analytical structure to the data for a plethora of downstream applications such as speech recognition and text analytics. NLP helps computers communicate with humans in their own language and scales other language-centric tasks. For example, NLP makes it possible for computers to read text, listen to speech, interpret conversations, measure sentiment, and determine which segments are important. Even though budgets were hit hard by the pandemic, 53% of technical leaders said their NLP budget was at least 10% higher compared to 2019 . In addition, many NLP breakthroughs are moving from research to production, with much coming from recent NLP research.

The last couple of years have been big for NLP with a number of high-profile research efforts involving: generative pre-training model (GPT), transfer learning, transformers (e.g. BERT, ELMO), multilingual NLP, training models with reinforcement learning, automating customer service with a new era of chatbots, NLP for social media monitoring, fake news detection, and so much more. 

In this article, I’ll help get you up to speed with current NLP research efforts by curating a list of the top recent papers published with a variety of research destinations including: arXiv.org , The International Conference on Learning Representations (ICLR) , The Stanford NLP Group , NeurIPS , and KDD . Enjoy!

ALBERT: A Lite BERT for Self-supervised Learning of Language Representations

Increasing model size when pretraining natural language representations often result in improved performance on downstream tasks. However, at some point, further model increases become harder due to GPU/TPU memory limitations and longer training times. To address these problems, this paper presents two parameter-reduction techniques to lower memory consumption and increase the training speed of BERT. Comprehensive empirical evidence shows that the proposed methods lead to models that scale much better compared to the original BERT. Also used is a self-supervised loss that focuses on modeling inter-sentence coherence, and shows it consistently helps downstream tasks with multi-sentence inputs. As a result, the best model from this NLP research establishes new state-of-the-art results on the GLUE, RACE, and \squad benchmarks while having fewer parameters compared to BERT-large. The GitHub repo associated with this paper can be found HERE . 

CogLTX: Applying BERT to Long Texts

BERTs are incapable of processing long texts due to quadratically increasing memory and time consumption. The attempts to address this problem, such as slicing the text by a sliding window or simplifying transformers, suffer from insufficient long-range attentions or need customized CUDA kernels. The limited text length of BERT reminds us of the limited capacity (5 ∼ 9 chunks) of the working memory of humans – then how do human beings “Cognize Long TeXts?” Founded on the cognitive theory stemming from Baddeley, the CogLTX framework described in this NLP research paper identifies key sentences by training a judge model, concatenates them for reasoning, and enables multi-step reasoning via rehearsal and decay. Since relevance annotations are usually unavailable, it is proposed to use treatment experiments to create supervision. As a general algorithm, CogLTX outperforms or gets comparable results to SOTA models on NewsQA, HotpotQA, multi-class, and multi-label long-text classification tasks with memory overheads independent of the text length.

ELECTRA: Pre-training Text Encoders as Discriminators Rather Than Generators

Masked language modeling (MLM) pre-training methods such as BERT corrupt the input by replacing some tokens with [MASK] and then train a model to reconstruct the original tokens. While they produce good results when transferred to downstream NLP tasks, they generally require large amounts of compute to be effective. As an alternative, this NLP research paper proposes a more sample-efficient pre-training task called replaced token detection . Instead of masking the input, the new approach corrupts it by replacing some tokens with plausible alternatives sampled from a small generator network. Then, instead of training a model that predicts the original identities of the corrupted tokens, the new approach trains a discriminative model that predicts whether each token in the corrupted input was replaced by a generator sample or not. Thorough experiments demonstrate this new pre-training task is more efficient than MLM because the task is defined over all input tokens rather than just the small subset that was masked out. As a result, the contextual representations learned by this approach substantially outperform the ones learned by BERT given the same model size, data, and compute. 

Retrieval-Augmented Generation for Knowledge-Intensive NLP Tasks

Large pre-trained language models have been shown to store factual knowledge in their parameters, and achieve state-of-the-art results when fine-tuned on downstream NLP tasks. However, their ability to access and precisely manipulate knowledge is still limited, and hence on knowledge-intensive tasks, their performance lags behind task-specific architectures. Additionally, providing provenance for their decisions and updating their world knowledge remain open research problems. Pre-trained models with a differentiable access mechanism to explicit non-parametric memory can overcome this issue, but have so far been only investigated for extractive downstream tasks. This NLP research paper explores a general-purpose fine-tuning recipe for retrieval-augmented generation (RAG) — models which combine pre-trained parametric and non-parametric memory for language generation. RAG models are introduced where the parametric memory is a pre-trained seq2seq model and the non-parametric memory is a dense vector index of Wikipedia, accessed with a pre-trained neural retriever. Two RAG formulations are compared, one which conditions on the same retrieved passages across the whole generated sequence, the other can use different passages per token.

ConvBERT: Improving BERT with Span-based Dynamic Convolution

Pre-trained language models like BERT and its variants have recently achieved impressive performance in various natural language understanding tasks. However, BERT heavily relies on the global self-attention block and thus suffers a large memory footprint and computation cost. Although all its attention heads query on the whole input sequence for generating the attention map from a global perspective, some heads only need to learn local dependencies, which means the existence of computation redundancy. This NLP research paper proposes a novel span-based dynamic convolution to replace these self-attention heads to directly model local dependencies. The novel convolution heads, together with the rest self-attention heads, form a new mixed attention block that is more efficient at both global and local context learning. BERT is equipped with this mixed attention design using a ConvBERT model. Experiments have shown that ConvBERT significantly outperforms BERT and its variants in various downstream tasks, with lower training costs and fewer model parameters. 

The Lottery Ticket Hypothesis for Pre-trained BERT Networks

In NLP, enormous pre-trained models like BERT have become the standard starting point for training on a range of downstream tasks, and similar trends are emerging in other areas of deep learning. In parallel, work on the lottery ticket hypothesis has shown that models for NLP and computer vision contain smaller matching subnetworks capable of training in isolation to full accuracy and transferring to other tasks. The work in this paper combines these observations to assess whether such trainable, transferrable subnetworks exist in pre-trained BERT models. For a range of downstream tasks, matching subnetworks at 40% to 90% sparsity is found. These subnetworks are found at (pre-trained) initialization, a deviation from prior NLP research where they emerge only after some amount of training. Subnetworks found on the masked language modeling task (the same task used to pre-train the model) transfer universally; those found on other tasks transfer in a limited fashion if at all. As large-scale pre-training becomes an increasingly central paradigm in deep learning, the results demonstrate that the main lottery ticket observations remain relevant in this context. The GitHub repo associated with this paper can be found HERE .

BERT Loses Patience: Fast and Robust Inference with Early Exit

This NLP research paper proposes Patience-based Early Exit , a straightforward yet effective inference method that can be used as a plug-and-play technique to simultaneously improve the efficiency and robustness of a pretrained language model (PLM). To achieve this, the approach couples an internal-classifier with each layer of a PLM and dynamically stops inference when the intermediate predictions of the internal classifiers do not change for a pre-defined number of steps. The approach improves inference efficiency as it allows the model to predict with fewer layers. Meanwhile, experimental results with an ALBERT model show that the method can improve the accuracy and robustness of the model by preventing it from overthinking and exploiting multiple classifiers for prediction, yielding a better accuracy-speed trade-off compared to existing early exit methods.

The Curious Case of Neural Text Degeneration

Despite considerable advancements with deep neural language models, the enigma of neural text degeneration persists when these models are tested as text generators. The counter-intuitive empirical observation is that even though the use of likelihood as a training objective leads to high-quality models for a broad range of language understanding tasks, using likelihood as a decoding objective leads to text that is bland and strangely repetitive. This NLP research paper reveals surprising distributional differences between human text and machine text. In addition, it’s found that decoding strategies alone can dramatically affect the quality of machine text, even when generated from exactly the same neural language model. The findings motivate Nucleus Sampling , a simple but effective method to draw the best out of neural generation. By sampling text from the dynamic nucleus of the probability distribution, which allows for diversity while effectively truncating the less reliable tail of the distribution, the resulting text better demonstrates the quality of human text, yielding enhanced diversity without sacrificing fluency and coherence.

Encoding word order in complex embeddings

Sequential word order is important when processing text. Currently, neural networks (NNs) address this by modeling word position using position embeddings. The problem is that position embeddings capture the position of individual words, but not the ordered relationship (e.g., adjacency or precedence) between individual word positions. This NLP research paper presents a novel and principled solution for modeling both the global absolute positions of words and their order relationships. The solution generalizes word embeddings, previously defined as independent vectors, to continuous word functions over a variable (position). The benefit of continuous functions over variable positions is that word representations shift smoothly with increasing positions. Hence, word representations in different positions can correlate with each other in a continuous function. The general solution of these functions is extended to a complex-valued domain due to richer representations. CNN, RNN, and Transformer NNs are extended to complex-valued versions to incorporate complex embedding. 

Stanza: A Python Natural Language Processing Toolkit for Many Human Languages

This paper introduces Stanza , an open-source Python natural language processing toolkit supporting 66 human languages. Compared to existing widely used toolkits, Stanza features a language-agnostic fully neural pipeline for text analysis, including tokenization, multi-word token expansion, lemmatization, part-of-speech and morphological feature tagging, dependency parsing, and named entity recognition. Stanza was trained on a total of 112 datasets, including the Universal Dependencies treebanks and other multilingual corpora, and show that the same neural architecture generalizes well and achieves competitive performance on all languages tested. Additionally, Stanza includes a native Python interface to the widely used Java Stanford CoreNLP software, which further extends its functionality to cover other tasks such as coreference resolution and relation extraction. The GitHub repo associated with this NLP research paper, along with source code, documentation, and pretrained models for 66 languages can be found HERE . 

Mogrifier LSTM

Many advances in NLP have been based upon more expressive models for how inputs interact with the context in which they occur. Recurrent networks, which have enjoyed a modicum of success, still lack the generalization and systematicity ultimately required for modeling language. This NLP research paper proposes an extension to the venerable Long Short-Term Memory (LSTM) in the form of mutual gating of the current input and the previous output. This mechanism affords the modeling of a richer space of interactions between inputs and their context. Equivalently, the model can be viewed as making the transition function given by the LSTM context-dependent. 

DeFINE: Deep Factorized Input Token Embeddings for Neural Sequence Modeling

For sequence models with large vocabularies, a majority of network parameters lie in the input and output layers. This NLP research paper describes a new method, DeFINE, for learning deep token representations efficiently. The architecture uses a hierarchical structure with novel skip-connections which allows for the use of low dimensional input and output layers, reducing total parameters and training time while delivering similar or better performance versus existing methods. DeFINE can be incorporated easily in new or existing sequence models. Compared to state-of-the-art methods including adaptive input representations, this technique results in a 6% to 20% drop in perplexity. 

FreeLB: Enhanced Adversarial Training for Natural Language Understanding

Adversarial training, which minimizes the maximal risk for label-preserving input perturbations, has proved to be effective for improving the generalization of language models. This paper proposes a novel adversarial training algorithm, FreeLB, that promotes higher invariance in the embedding space, by adding adversarial perturbations to word embeddings and minimizing the resultant adversarial risk inside different regions around input samples. To validate the effectiveness of the proposed approach, it is applied to Transformer-based models for natural language understanding and commonsense reasoning tasks. Experiments on the GLUE benchmark show that when applied only to the finetuning stage, it is able to improve the overall test scores of BERT-base model from 78.3 to 79.4, and RoBERTa-large model from 88.5 to 88.8. The GitHub repo associated with this paper can be found HERE . 

Dynabench: Rethinking Benchmarking in NLP

This paper introduces Dynabench, an open-source platform for dynamic dataset creation and model benchmarking. Dynabench runs in a web browser and supports human-and-model-in-the-loop dataset creation: annotators seek to create examples that a target model will misclassify, but that another person will not. It is argued that Dynabench addresses a critical need in the NLP community: contemporary models quickly achieve outstanding performance on benchmark tasks but nonetheless fail on simple challenge examples and falter in real-world scenarios. With Dynabench, dataset creation, model development, and model assessment can directly inform each other, leading to more robust and informative benchmarks. The paper reports on four initial NLP tasks, illustrating these concepts and highlighting the promise of the platform, and address potential objections to dynamic benchmarking as a new standard for the field.

Causal Effects of Linguistic Properties

This paper considers the problem of using observational data to estimate the causal effects of linguistic properties. For example, does writing a complaint politely lead to a faster response time? How much will a positive product review increase sales? This paper addresses two technical challenges related to the problem before developing a practical method. First, formalize the causal quantity of interest as the effect of a writer’s intent, and establish the assumptions necessary to identify this from observational data. Second, in practice, access is only offered to noisy proxies for the linguistic properties of interest—e.g., predictions from classifiers and lexicons. An estimator is proposed for this setting and proof that its bias is bounded when we perform an adjustment for the text. Based on these results, TEXTCAUSE is introduced, an algorithm for estimating causal effects of linguistic properties. The method leverages (1) distant supervision to improve the quality of noisy proxies, and (2) a pre-trained language model (BERT) to adjust for the text. It is shown that the proposed method outperforms related approaches when estimating the effect of Amazon review sentiment on semi-simulated sales figures.

LM-Critic: Language Models for Unsupervised Grammatical Error Correction

Training a model for grammatical error correction (GEC) requires a set of labeled ungrammatical/grammatical sentence pairs, but manually annotating such pairs can be expensive. Recently, the Break-It-Fix-It (BIFI) framework has demonstrated strong results on learning to repair a broken program without any labeled examples, but this relies on a perfect critic (e.g., a compiler) that returns whether an example is valid or not, which does not exist for the GEC task. This paper shows how to leverage a pretrained language model (LM) in defining an LM-Critic, which judges a sentence to be grammatical if the LM assigns it a higher probability than its local perturbations. This LM-Critic and BIFI is applied along with a large set of unlabeled sentences to bootstrap realistic ungrammatical/grammatical pairs for training a corrector. 

Generative Adversarial Transformers

This paper introduces the GANformer, a novel and efficient type of transformer, and explores it for the task of visual generative modeling. The network employs a bipartite structure that enables long-range interactions across the image, while maintaining computation of linear efficiency, that can readily scale to high-resolution synthesis. It iteratively propagates information from a set of latent variables to the evolving visual features and vice versa, to support the refinement of each in light of the other and encourage the emergence of compositional representations of objects and scenes. In contrast to the classic transformer architecture, it utilizes multiplicative integration that allows flexible region-based modulation, and can thus be seen as a generalization of the successful StyleGAN network. The model’s strength and robustness are demonstrated through a careful evaluation over a range of datasets, from simulated multi-object environments to rich real-world indoor and outdoor scenes, showing it achieves state-of-the-art results in terms of image quality and diversity, while enjoying fast learning and better data efficiency. The GitHub repo associated with this paper can be found HERE .

Learn More About NLP and NLP Research at ODSC West 2021

At our upcoming event this November 16th-18th in San Francisco,  ODSC West 2021 will feature a plethora of talks, workshops, and training sessions on NLP and NLP research. You can register now for 30% off all ticket types before the discount drops to 20% in a few weeks. Some highlighted sessions on NLP and NLP research  include:

• Transferable Representation in Natural Language Processing: Kai-Wei Chang, PhD | Director/Assistant Professor | UCLA NLP/UCLA CS
• Build a Question Answering System using DistilBERT in Python: Jayeeta Putatunda | Data Scientist | MediaMath
• Introduction to NLP and Topic Modeling: Zhenya Antić, PhD | NLP Consultant/Founder | Practical Linguistics Inc
• NLP Fundamentals: Leonardo De Marchi | Lead Instructor | ideai.io

Sessions on Deep Learning and Deep Learning Research:

• GANs: Theory and Practice, Image Synthesis With GANs Using TensorFlow: Ajay Baranwal | Center Director | Center for Deep Learning in Electronic Manufacturing, Inc
• Machine Learning With Graphs: Going Beyond Tabular Data: Dr. Clair J. Sullivan | Data Science Advocate | Neo4j
• Deep Dive into Reinforcement Learning with PPO using TF-Agents & TensorFlow 2.0: Oliver Zeigermann | Software Developer | embarc Software Consulting GmbH
• Get Started with Time-Series Forecasting using the Google Cloud AI Platform: Karl Weinmeister | Developer Relations Engineering Manager | Google

Sessions on Machine Learning:

• Towards More Energy-Efficient Neural Networks? Use Your Brain!: Olaf de Leeuw | Data Scientist | Dataworkz
• Practical MLOps: Automation Journey: Evgenii Vinogradov, PhD | Head of DHW Development | YooMoney
• Applications of Modern Survival Modeling with Python: Brian Kent, PhD | Data Scientist | Founder The Crosstab Kite
• Using Change Detection Algorithms for Detecting Anomalous Behavior in Large Systems: Veena Mendiratta, PhD | Adjunct Faculty, Network Reliability, and Analytics Researcher | Northwestern University

Daniel Gutierrez, ODSC

Daniel D. Gutierrez is a practicing data scientist who’s been working with data long before the field came in vogue. As a technology journalist, he enjoys keeping a pulse on this fast-paced industry. Daniel is also an educator having taught data science, machine learning and R classes at the university level. He has authored four computer industry books on database and data science technology, including his most recent title, “Machine Learning and Data Science: An Introduction to Statistical Learning Methods with R.” Daniel holds a BS in Mathematics and Computer Science from UCLA.

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Participants continued to live in their home environment without any prescribed diet or physical activity during the 28 consecutive days of the study. Error bars are SEs of the mean. The vertical dashed line separates the two 2-week sleep periods.

A-D, Data are in ascending order of change in sleep duration for the control group and sleep extension group. E, Data were from 74 participants. All available data were used. The line represents the line of best fit from the linear regression model. One participant in the control group and 3 participants in the sleep extension group had missing data in change in sleep duration (ie, missing mean data in at least 1 of 2 study periods). One participant in the control group and 4 participants in the sleep extension group had missing data in change in energy intake. Overall, 1 participant in the control group and 5 participants in the sleep extension group had missing data in either change in sleep duration or change in energy intake.

Trial Protocol

eMethods. Participants, Inclusion and Exclusion Criteria

eReferences

eTable 1. Effect of Treatment on Actigraphy-Based Time in Bed and Sleep Duration on All Days, Workdays and Free Days

eTable 2. Effect of Treatment on Actigraphy-Based Outcomes

eTable 3. Baseline Characteristics of Participants With Complete vs Incomplete Data

eTable 4. Self-Reported Outcomes by Visual Analog Scales

Data Sharing Statement

• Good Sleep, Better Life—Enhancing Health and Safety With Optimal Sleep JAMA Internal Medicine Invited Commentary April 1, 2022 Mark R. Rosekind, PhD; Rafael Pelayo, MD; Debra A. Babcock, MD

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Tasali E , Wroblewski K , Kahn E , Kilkus J , Schoeller DA. Effect of Sleep Extension on Objectively Assessed Energy Intake Among Adults With Overweight in Real-life Settings : A Randomized Clinical Trial . JAMA Intern Med. 2022;182(4):365–374. doi:10.1001/jamainternmed.2021.8098

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Effect of Sleep Extension on Objectively Assessed Energy Intake Among Adults With Overweight in Real-life Settings : A Randomized Clinical Trial

• 1 Department of Medicine, The University of Chicago, Chicago, Illinois
• 2 Department of Public Health Sciences, The University of Chicago, Chicago, Illinois
• 3 Biotechnology Center, Department of Nutritional Sciences, University of Wisconsin–Madison, Madison
• Invited Commentary Good Sleep, Better Life—Enhancing Health and Safety With Optimal Sleep Mark R. Rosekind, PhD; Rafael Pelayo, MD; Debra A. Babcock, MD JAMA Internal Medicine

Question   What is the effect of sleep extension on objectively assessed energy intake in adults with overweight in their usual home environment?

Findings   In this randomized clinical trial of 80 adults with overweight and habitual sleep less than 6.5 hours per night, those randomized to a 2-week sleep extension intervention significantly reduced their daily energy intake by approximately 270 kcal compared with the control group. Total energy expenditure did not significantly differ between the sleep extension and control groups, resulting in a negative energy balance with sleep extension.

Meaning   The findings suggest that improving and maintaining adequate sleep duration could reduce weight and be a viable intervention for obesity prevention and weight loss programs.

Importance   Short sleep duration has been recognized as a risk factor for obesity. Whether extending sleep duration may mitigate this risk remains unknown.

Objective   To determine the effects of a sleep extension intervention on objectively assessed energy intake, energy expenditure, and body weight in real-life settings among adults with overweight who habitually curtailed their sleep duration.

Design, Setting, and Participants   This single-center, randomized clinical trial was conducted from November 1, 2014, to October 30, 2020. Participants were adults aged 21 to 40 years with a body mass index (calculated as weight in kilograms divided by height in meters squared) between 25.0 and 29.9 and had habitual sleep duration of less than 6.5 hours per night. Data were analyzed according to the intention-to-treat principle.

Interventions   After a 2-week habitual sleep period at baseline, participants were randomized to either an individualized sleep hygiene counseling session that was intended to extend their bedtime to 8.5 hours (sleep extension group) or to continue their habitual sleep (control group). All participants were instructed to continue daily routine activities at home without any prescribed diet or physical activity.

Main Outcomes and Measures   The primary outcome was change in energy intake from baseline, which was objectively assessed as the sum of total energy expenditure and change in body energy stores. Total energy expenditure was measured by the doubly labeled water method. Change in body energy stores was computed using regression of daily home weights and body composition changes from dual-energy x-ray absorptiometry. Sleep duration was monitored by actigraphy. Changes from baseline were compared between the 2 groups using intention-to-treat analysis.

Results   Data from 80 randomized participants (mean [SD] age, 29.8 [5.1] years; 41 men [51.3%]) were analyzed. Sleep duration was increased by approximately 1.2 hours per night (95% CI, 1.0 to 1.4 hours; P  < .001) in the sleep extension group vs the control group. The sleep extension group had a significant decrease in energy intake compared with the control group (−270 kcal/d; 95% CI, −393 to −147 kcal/d; P  < .001). The change in sleep duration was inversely correlated with the change in energy intake ( r  = −0.41; 95% CI, −0.59 to −0.20; P  < .001). No significant treatment effect in total energy expenditure was found, resulting in weight reduction in the sleep extension group vs the control group.

Conclusions and Relevance   This trial found that sleep extension reduced energy intake and resulted in a negative energy balance in real-life settings among adults with overweight who habitually curtailed their sleep duration. Improving and maintaining healthy sleep duration over longer periods could be part of obesity prevention and weight loss programs.

Trial Registration   ClinicalTrials.gov Identifier: NCT02253368

Obesity is a major public health concern. 1 The obesity epidemic appears to coincide with a pattern of sleeping less that has been observed in society over the past several decades. For example, one-third of the US population reported not getting the recommended 7 to 9 hours of sleep per night. 2 - 4 Substantial evidence suggests that sleeping less than 7 hours per night on a regular basis is associated with adverse health consequences. 5 Particularly, insufficient sleep duration has been increasingly recognized as an important risk factor for obesity. 6 , 7 Prospective epidemiologic studies suggest that short sleep duration is an important risk factor for weight gain. 8 - 10 However, it remains unknown whether extending sleep duration can be an effective strategy for preventing or reversing obesity. Although sleep hygiene education is encouraged by obesity experts, 11 most health professionals and patients do not implement obtaining adequate sleep duration as part of the strategies to combat the obesity epidemic. 12

At the population level, the association between energy flux and body weight implicates that increased energy intake is the main factor in higher body weights in modern society. 13 According to dynamic prediction models, a sustained increase in energy intake of even 100 kcal/d would result in a weight gain of about 4.5 kg over 3 years. 14 , 15 Factors that underlie the observed persistent increase in energy intake and mean weight gain at the population level need to be better understood. One such factor is insufficient sleep duration. Short-term experimental laboratory studies have found that sleep restriction in healthy individuals is associated with an increased mean energy intake of about 250 to 350 kcal/d with minimal to no change in energy expenditure. 16 - 19 However, these laboratory studies do not represent real life. The magnitude of sleep restriction was extreme in most cases, and energy intake was ascertained from a single or a few meals. In a real-life setting in which participants continue their normal daily activities, multiple interacting factors (eg, social interactions and free-living physical activity) can influence energy intake or expenditure and weight.

To date, it remains unknown whether and to what extent an intervention that is intended to increase sleep duration in a real-life setting affects energy balance and body weight. We conducted a randomized clinical trial (RCT) to determine the effects of a sleep extension intervention on objectively assessed energy intake, energy expenditure, and body weight in real-life settings among adults with overweight who habitually curtailed their sleep duration.

This single-center, parallel-group RCT was conducted from November 1, 2014, to October 30, 2020. The protocol was approved by The University of Chicago Institutional Review Board, and participants provided written informed consent. The study protocol is available in Supplement 1 . We followed the Consolidated Standards of Reporting Trials ( CONSORT ) reporting guideline.

Adult men and women aged 21 to 40 years with a body mass index (calculated as weight in kilograms divided by height in meters squared) between 25.0 and 29.9 and a mean habitual sleep duration of less than 6.5 hours per night were eligible. Individuals were required to have stable self-reported sleep habits for the past 6 months. They were recruited from the community and completed an initial online survey followed by a face-to-face interview. Race and ethnicity data were self-reported at this time and included the following race and ethnicity categories: Asian, Black or African American, Hispanic, and White. Those who met the inclusion criteria underwent laboratory screening (polysomnography, oral glucose tolerance test, and blood tests) to determine eligibility. Habitual sleep duration was confirmed by a 1-week screening wrist actigraphy at home. Those who had obstructive sleep apnea confirmed by laboratory polysomnography (apnea-hypopnea index >5), insomnia or history of any other sleep disorder, or night shift and rotating shift work (current or in the past 2 years) were excluded. Detailed eligibility criteria are provided in the eMethods in Supplement 2 .

After a 2-week habitual sleep period at baseline, participants were randomized to either 2-week sleep extension (sleep extension group) or 2-week continued habitual sleep (control group) ( Figure 1 ). Participants continued their daily routine activities at home without any prescribed diet or physical activity.

To blind participants to the sleep extension intervention, we described the study in the recruitment materials as follows: “we will collect information about sleep habits and metabolism.” The sleep extension group was blinded to randomization until after the 2-week baseline assessments, and the control group was blinded until the end of the 4-week study. This approach allowed us to capture habitual sleep-wake patterns without influencing participants' usual behavior or creating selection bias with only participants interested in improving sleep habits. After study completion, all participants were provided with information about the health benefits of optimal sleep duration. Block randomization, stratified by sex, was performed using computer-generated random numbers. Before the trial, randomization assignments were prepared by a biostatistician (K.W.) using opaque, sealed, and numbered envelopes and were given to the research coordinator (E.K.).

Sleep-wake patterns were continuously monitored at home by wrist actigraphy throughout the 4-week study. Participants were asked to wear an accelerometer (motion)-based monitor (Actiwatch Spectrum Plus; Philips) and to press a built-in event marker button when they went to bed to sleep each night and when they got out of bed each morning. Sleep was automatically scored (Actiware, version 6.0.9; Philips) using validated algorithms as the sum of all epochs that were scored as sleep during the total time spent in bed. 20 , 21

During the 2-week baseline, all participants were instructed to continue their habitual sleep patterns at home. On the morning of day 15, participants met with study investigators (E.T. and E.K.) in the research center. Those who were randomized to the sleep extension group received individualized sleep hygiene counseling through a structured interview (E.T.) (eMethods in Supplement 2 ). 22 At the end of the interview, participants were provided with individualized recommendations to follow at home for 2 weeks, with the aim of extending their bedtime duration to 8.5 hours. On day 22, participants returned for a brief follow-up visit. Actigraphy data from the first intervention week were reviewed, and further sleep counseling was provided as needed.

To minimize any imbalance in contact with the investigators between the 2 groups, we asked participants in the control group to meet with the study investigators on days 15 and 22. Actigraphy data of these participants were downloaded, but the participants did not receive any specific sleep recommendations and were instructed to continue their daily routine and habitual sleep behaviors until the end of the study.

For each 2-week period, the energy intake was calculated from the sum of total energy expenditure and change in body energy stores using the principle of energy balance. 14 , 23 , 24 Total energy expenditure was measured by the doubly labeled water method. 25 - 29 For each 2-week period, the change in body energy stores was computed from the regression (slope, grams per day) of daily home weights and change in body composition (ie, fat mass and fat-free mass) using dual-energy x-ray absorptiometry. Participants were provided a cellular-enabled weight scale (BodyTrace; BodyTrace Inc) and instructed to take their nude weights twice every morning after awakening before eating or drinking. Weight values were hidden from the participants to minimize potential influence on behavior. Changes in body composition were converted to changes in energy stores using 9.5 kcal/g as the energy coefficient of fat mass and 1.0 kcal/g as the energy coefficient of fat-free mass. 30 Resting metabolic rate was measured by indirect calorimetry for 30 minutes after fasting and for 4 hours after eating a standardized breakfast. Thermic effect of the meal was calculated, which was previously described elsewhere. 31 Activity energy expenditure was calculated by subtracting the resting metabolic rate and thermic effect of the meal from the total energy expenditure. 31 , 32 Additional details are provided in the eMethods in Supplement 2 .

The primary outcome was change in energy intake from baseline. A total final sample size of 80 participants (40 per group) was originally planned and provided 80% power to detect a true difference in energy intake between groups of 207 kcal/d using a 2-sided α = .05 significance threshold (trial protocol in Supplement 1 ). An intention-to-treat analysis was conducted in Stata, version 16 (StataCorp LLC) using 2-tailed tests with statistical significance set at P  < .05. Categorical data are presented as counts and percentages. Continuous data are presented as means and SDs. Linear mixed-effects models were fit to determine the treatment differences between the groups. 33 Models included the randomization group, 2-week baseline period (period 1) vs 2-week intervention (period 2) and their interaction, and random effects for each participant. The treatment effect (95% CI) was estimated by the treatment group and period interaction, which is equivalent to testing the difference in change from baseline (period 2 minus period 1) in the sleep extension group vs the control group. To confirm the robustness of primary findings, we fit additional models using the analysis of covariance approach with the period 2 value as the dependent variable, treatment group as the independent variable, and period 1 value as covariates.

In secondary analyses, mixed models that adjusted for sex or menstrual cycle were also fit; these covariates were chosen because of the known influence of menstrual cycle on short-term changes in weight. A Pearson correlation coefficient was calculated to assess the relationships between the changes from baseline in sleep duration and the changes from baseline in energy intake. No adjustments were made to P values or CIs for multiple comparisons. Baseline characteristics of participants with complete data were compared with those of participants with incomplete data using unpaired, 2-tailed t tests and Fisher exact tests. No imputation for missing values was performed.

Of the 210 adults who provided consent and were assessed for eligibility, 81 were randomized (41 to the control group and 40 to the sleep extension group) initially ( Figure 1 ). One participant in the control group revealed adhering to a weight loss regimen and thus did not meet the study inclusion criteria and was deemed ineligible after randomization. 34 The 80 participants had a mean (SD) age of 29.8 (5.1) years and consisted of 41 men (51.3%) and 39 women (48.7%). Baseline characteristics of participants were similar between randomization groups ( Table 1 ). None of the participants were using any antihypertensive or lipid-lowering agents or any prescription medication that can affect sleep or metabolism.

Figure 2 illustrates the mean nightly sleep duration by actigraphy in each group throughout the 4-week study. Participants in the sleep extension group had a significant increase from baseline in mean sleep duration by actigraphy compared with those in the control group (1.2 hours; 95% CI, 1.0-1.4 hours; P  < .001). The findings were similar with regard to change in sleep duration when only participants' workdays (1.3 hours; 95% CI, 1.0-1.5 hours; P  < .001) or free days (1.1 hours; 95% CI, 0.7-1.5 hours; P  < .001) were considered (eTable 1 in Supplement 2 ). No difference was found in change in sleep efficiency (percentage of time spent asleep during time in bed) between the 2 groups (–0.6 hours; 95% CI, –2.1 to 1.0 hours; P  = .48), confirming the success of the intervention (eTable 2 in Supplement 2 ).

Energy intake was statistically significantly decreased in the sleep extension group compared with the control group (−270.4 kcal/d; 95% CI, −393.4 to −147.4 kcal/d; P  < .001). Figure 3 A through D illustrates the changes from baseline in energy intake and the changes from baseline in sleep duration in individual participants. There was a significant increase in energy intake from baseline in the control group (114.9 kcal/d; 95% CI, 29.6 to 200.2 kcal/d) and a significant decrease in energy intake from baseline in the sleep extension group (−155.5 kcal/d; 95% CI, −244.1 to −66.9 kcal/d) ( Table 2 ). Considering all participants, the change in sleep duration was inversely correlated with the change in energy intake ( r  = −0.41; 95% CI, −0.59 to −0.20; P  < .001) ( Figure 3 E). Each 1-hour increase in sleep duration was associated with a decrease in energy intake of approximately 162 kcal/d (−162.3 kcal/d; 95% CI, −246.8 to −77.7 kcal/d; P  < .001).

No statistically significant treatment effect was found in total energy expenditure or other measures of energy expenditure ( Table 2 ). Participants in the sleep extension group had a statistically significant reduction in weight compared with those in the control group (−0.87 kg; 95% CI, −1.39 to −0.35 kg; P  = .001). There was weight gain from baseline in the control group (0.39 kg; 95% CI, 0.02 to 0.76 kg) and weight reduction from baseline in the sleep extension group (−0.48 kg; 95% CI, −0.85 to −0.11 kg) ( Table 2 ).

The findings on energy intake, energy expenditure, and weight were similar after adjustment for the effects of sex or menstrual cycle. No statistically significant differences in baseline characteristics were found between the 75 participants (93.8%) who had complete data on energy intake (primary outcome) vs participants with missing data on energy intake. The proportion of participants with complete data on energy intake was not significantly different between the sleep extension and control groups (90.0% vs 97.5%; P  = .36). When all reported outcomes were considered, no significant differences (except for depressive symptoms) in baseline characteristics were found between participants with complete data and participants with incomplete or missing data (eTable 3 in Supplement 2 ). The proportion of participants with complete data on all reported outcomes was similar between the sleep extension and control groups (82.5% vs 85.0%; P  > .99).

In this RCT of adults with overweight who habitually curtailed their sleep duration, sleep extension reduced energy intake and resulted in a negative energy balance (ie, energy intake that is less than energy expenditure) in real-life settings. To our knowledge, this study provides the first evidence of the beneficial effects of extending sleep to a healthy duration on objectively assessed energy intake and body weight in participants who continued to live in their home environment. Modest lifestyle changes in energy intake or expenditure are increasingly promoted as viable interventions to reverse obesity.

According to the Hall dynamic prediction model, a decrease in energy intake of approximately 270 kcal/d, which we observed after short-term sleep extension, would predict an approximately 12-kg weight loss over 3 years if the effects were sustained over a long term. 14 , 15 However, this study cannot infer how long healthy sleep habits may be sustained. Nevertheless, these modeling predictions on weight change suggest that continued adequate sleep duration and beneficial effect on energy intake could translate into clinically meaningful weight loss and help reverse or prevent obesity. Thus, the findings of this study may have important public health implications for weight management and policy recommendations.

The findings of decreased energy intake, negative energy balance, and weight reduction resulting from sleep extension are in agreement with the findings of short-term laboratory sleep-restriction studies showing increased energy intake and weight gain 17 as well as the findings of prospective epidemiologic studies linking sleep restriction to obesity risk. 8 A recent meta-analysis of randomized controlled laboratory studies found that short-term sleep restriction over 1 to 14 days of duration in healthy individuals was associated with increases of mean energy intake by approximately 253 kcal/d, as assessed during a single meal. 17 Another meta-analysis of prospective cohort studies found that the risk of obesity increased by 9% for each 1-hour decrease in sleep duration. 8 We did not observe a statistically significant change in total energy expenditure by doubly labeled water method or mean daytime activity counts by actigraphy (eTable 2 in Supplement 2 ). Although some laboratory sleep-restriction studies reported an increase in total energy expenditure of approximately 92 to 111 kcal/d, using a whole-room calorimeter, 35 , 36 other studies observed no change. 16 , 37 We found a modest reduction in weight after sleep extension, and the composition of weight change was primarily in fat-free mass, which is consistent with the short-term changes in body composition. 38 , 39 If sleep is extended over longer periods, weight loss in the form of fat mass would likely increase over time. A few observations suggest that sleeping 7 to 8 hours per night is associated with greater success in weight loss interventions. 40 - 43

In this RCT, we found an overall increase in objective sleep duration of approximately 1.2 hours in participants who habitually slept less than 6.5 hours per night. The change in sleep duration from baseline varied between participants and from night to night in the real-life setting. Overall, the sleep extension group compared with the control group had significantly higher subjective scores in obtaining sufficient sleep, with more daytime energy and alertness and better mood (eTable 4 in Supplement 2 ). Similar to a previous study of sleep extension, 22 the present RCT used an individualized counseling approach. Another study used bedtime extension in habitual short sleepers in real-life conditions but obtained variable benefits on sleep, likely because of a lack of an individualized approach or appropriate blinding. 44 None of these previous studies objectively measured energy intake.

Future similarly rigorous intervention studies of longer duration and using objective assessments of energy balance under real-life conditions are warranted to elucidate the underlying mechanisms and to investigate whether sleep extension could be an effective, scalable strategy for reversing obesity in diverse populations. Along with a healthy diet and regular physical activity, healthy sleep habits should be integrated into public messages to help reduce the risk of obesity and related comorbidities.

This study has several strengths. The major strengths are the randomized design and the objective tracking of energy intake and sleep in real-life settings. Most epidemiologic studies linking short sleep duration to body weight relied on self-reported dietary intake. 45 We did not collect self-reported dietary data because this method is subject to bias and has been shown to be inaccurate compared with the doubly labeled water method. 46 , 47 Most experimental studies that measured energy intake used a single meal under unnatural laboratory conditions. We used a validated method to objectively track energy intake by the doubly labeled water method and change in energy stores. 23 , 48 , 49 In this trial, we objectively quantified energy intake after sleep extension while individuals continued their daily routine in their usual environment. Participant blinding and use of actigraphy allowed us to capture true habitual sleep patterns at baseline. 22 , 50 In addition, we excluded insomnia and sleep apnea.

This study also has several limitations. We enrolled adults with overweight and used selective eligibility criteria, which may limit generalizability to more diverse populations. The increase in energy intake and weight from baseline that we observed in the control group may have contributed to the significant treatment effects. However, in RCTs, performing a between-group comparison, rather than separate tests against baseline within the groups, is strongly recommended. 51 The study did not provide information on how long healthy sleep habits could be maintained over longer periods. 44 We did not systematically assess the factors that may have influenced sleep behavior, but limiting the use of electronic devices appeared to be a key intervention among the participants (eTable 4 in Supplement 2 ). The doubly labeled water method has a precision of 5%, which may translate into some degree of uncertainty in the energy intake calculations. Although whole-room calorimeters can measure energy expenditure with a higher precision of approximately 1% to 2%, they do not represent real-life measurement and are not feasible over longer periods. We did not assess the underlying biological mechanisms of food frequency and the circadian timing of food intake. Multiple interrelated factors could contribute to the finding of decreased energy intake after sleep extension. 6 , 52 Evidence from laboratory sleep restriction studies suggests that increased hunger, alterations in appetite-regulating hormones, and changes in brain regions related to reward-seeking behavior are potential mechanisms that promote overeating after sleep restriction. 6 , 45

This RCT found that short-term sleep extension reduced objectively measured energy intake and resulted in a negative energy balance in real-life settings in adults with overweight who habitually curtailed their sleep duration. The findings highlighted the importance of improving and maintaining adequate sleep duration as a public health target for obesity prevention and increasing awareness about the benefits of adequate sleep duration for healthy weight maintenance.

Accepted for Publication: November 14, 2021.

Published Online: February 7, 2022. doi:10.1001/jamainternmed.2021.8098

Open Access: This is an open access article distributed under the terms of the CC-BY License . © 2022 Tasali E et al. JAMA Internal Medicine .

Corresponding Author: Esra Tasali, MD, Department of Medicine, The University of Chicago, 5841 S Maryland Ave, Chicago, IL 60637 ( [email protected] ).

Author Contributions: Author Dr Tasali and Ms Wroblewski had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Tasali, Schoeller.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Tasali, Schoeller.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Tasali, Wroblewski.

Obtained funding: Tasali.

Administrative, technical, or material support: Tasali, Kahn, Kilkus, Schoeller.

Supervision: Tasali.

Other - research coordination duties: Kahn.

Conflict of Interest Disclosures: None reported.

Funding/Support: This study was funded by grants R01DK100426, CTSA-UL1 TR0002389, and UL1TR002389 from the National Institutes of Health and by the Diabetes Research and Training Center at The University of Chicago.

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Data Sharing Statement : See Supplement 3 .

Additional Contributions: Timothy Shriver, MS, University of Wisconsin–Madison, assisted with doubly labeled water measurements. Maureen Costello, MS, The University of Chicago, assisted with dual-energy x-ray absorptiometry scans. Becky Tucker, BA, Harry Whitmore, RPSGT, and Kristin Hoddy, PhD, RD, The University of Chicago, assisted with data collection. We thank the nurses, dieticians, and technicians at the Clinical Research Center at The University of Chicago for their expert assistance in data collection. We also thank the staff of the Sleep Research Center at The University of Chicago for their support. These individuals received no additional compensation, outside of their usual salary, for their contributions. We thank the volunteers for participating in this study.

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Collection  10 March 2022

Top 100 in Neuroscience

This collection highlights our most downloaded* neuroscience papers published in 2021. Featuring authors from around the world, these papers showcase valuable research from an international community.

*Data obtained from SN Inights, which is based on Digital Science's Dimensions.

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Character.AI CEO Noam Shazeer returns to Google

In a big move, Character.AI co-founder and CEO Noam Shazeer is returning to Google after leaving the company in October 2021 to found the a16z-backed chatbot startup. In his previous stint, Shazeer spearheaded the team of researchers that built  LaMDA  (Language Model for Dialogue Applications), a language model that was used for conversational AI tools .

Character.AI co-founder Daniel De Freitas is also joining Google with some other employees from the startup. Dominic Perella, Character.AI’s general counsel, is becoming an interim CEO at the startup. The company noted that most of the staff is staying at Character.AI.

Google is also signing a non-exclusive agreement with Character.AI to use its tech.

“I am super excited to return to Google and work as part of the Google DeepMind team. I am so proud of everything we built at Character.AI over the last 3 years. I am confident that the funds from the non-exclusive Google licensing agreement, together with the incredible Character.AI team, positions Character.AI for continued success in the future,” Shazeer said in a statement given to TechCrunch.

Google said that Shazeer is joining the DeepMind research team but didn’t specify his or De Freitas’s exact roles.

“We’re particularly thrilled to welcome back Noam, a preeminent researcher in machine learning, who is joining Google DeepMind’s research team, along with a small number of his colleagues,” Google said in a statement. “This agreement will provide increased funding for Character.AI to continue growing and to focus on building personalized AI products for users around the world,” a Google spokesperson said.

Character.AI has raised over $150 million in funding, largely from a16z.

“When Noam and Daniel started  Character.AI , our goal of personalized superintelligence required a full stack approach. We had to pre-train models, post-train them to power the experiences that make  Character.AI  special, and build a product platform with the ability to reach users globally,” Character AI mentioned in its blog announcing the move.

“Over the past two years, however, the landscape has shifted; many more pre-trained models are now available. Given these changes, we see an advantage in making greater use of third-party LLMs alongside our own. This allows us to devote even more resources to post-training and creating new product experiences for our growing user base.”

There is a possibility that different regulatory bodies, such as the Federal Trade Commission (FTC), and the Department of Justice (DoJ) in the U.S. and the EU will scrutinize these reverse acqui-hires closely. Last month. the U.K’s Competition and Markets Authority (CMA) issued a notice saying that it is looking into Microsoft hiring key people from Inflection AI to understand if the tech giant is trying to avoid regulatory oversight. The FTC opened a similar investigation in June to look into Microsoft’s $650 million deal.

You can reach out to this reporter at [email protected] by email and on signal at ivan.42 .

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