EKGs may soon screen for cardiomyopathy, thanks to AI – An AI-based approach to diagnostics could see electrocardiograms repurposed to screen for hypertrophic cardiomyopathy in the not-so-distant future @ Monitoring organs and cells in living fly larvae @ Scientists Have Held Individual Atoms for the Very First Time – It’s a quantum physics breakthrough. And it’s all thanks to some tweezers @ Crystal-stacking process can produce new materials for high-tech devices & Powerful antibiotic discovered using machine learning for first time – Team at MIT says halicin kills some of the world’s most dangerous strains @ Einstein’s Lost Theory Describes a Universe Without a Big Bang & SpaceX Starship Mega Stack Multi-View Time lapse – Video @ Article: A Community-Based Intervention for Managing Hypertension in Rural South Asia – The New England Journal of Medicine @ Links and images

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  • – > Mestrado – Dissertation – Tabelas, Figuras e Gráficos – Tables, Figures and Graphics´´My´´ Dissertation @ #Innovation #energy #life #health #Countries #Time #Researches #Reference #Graphics #Ages #Age #Mice #People #Person #Mouse #Genetics #PersonalizedMedicine #Diagnosis #Prognosis #Treatment #Disease #UnknownDiseases #Future #VeryEfficientDrugs #VeryEfficientVaccines #VeryEfficientTherapeuticalSubstances #Tests #Laboratories #Investments #Details #HumanLongevity #DNA #Cell #Memory #Physiology #Nanomedicine #Nanotechnology #Biochemistry #NewMedicalDevices #GeneticEngineering #Internet #History #Science #World

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The influence of physical activity in the progression of experimental lung cancer in mice

Renato Batista Paceli 1Rodrigo Nunes CalCarlos Henrique Ferreira dos SantosJosé Antonio CordeiroCassiano Merussi NeivaKazuo Kawano NagaminePatrícia Maluf Cury


GRUPO_AF1GROUP AFA1 – Aerobic Physical Activity – Atividade Física Aeróbia – ´´My´´ Dissertation – Faculty of Medicine of Sao Jose do Rio Preto

GRUPO AFAN 1GROUP AFAN1 – Anaerobic Physical ActivityAtividade Física Anaeróbia – ´´My´´ Dissertation – Faculty of Medicine of Sao Jose do Rio Preto

GRUPO_AF2GROUP AFA2 – Aerobic Physical ActivityAtividade Física Aeróbia – ´´My´´ Dissertation – Faculty of Medicine of Sao Jose do Rio Preto

GRUPO AFAN 2GROUP AFAN 2 – Anaerobic Physical ActivityAtividade Física Anaeróbia´´My´´ Dissertation – Faculty of Medicine of Sao Jose do Rio Preto

Slides – mestrado´´My´´ Dissertation – Faculty of Medicine of Sao Jose do Rio Preto



Avaliação da influência da atividade física aeróbia e anaeróbia na progressão do câncer de pulmão experimental – Summary – Resumo´´My´´ Dissertation Faculty of Medicine of Sao Jose do Rio Preto



Lung cancer is one of the most incident neoplasms in the world, representing the main cause of mortality for cancer. Many epidemiologic studies have suggested that physical activity may reduce the risk of lung cancer, other works evaluate the effectiveness of the use of the physical activity in the suppression, remission and reduction of the recurrence of tumors. The aim of this study was to evaluate the effects of aerobic and anaerobic physical activity in the development and the progression of lung cancer. Lung tumors were induced with a dose of 3mg of urethane/kg, in 67 male Balb – C type mice, divided in three groups: group 1_24 mice treated with urethane and without physical activity; group 2_25 mice with urethane and subjected to aerobic swimming free exercise; group 3_18 mice with urethane, subjected to anaerobic swimming exercise with gradual loading 5-20% of body weight. All the animals were sacrificed after 20 weeks, and lung lesions were analyzed. The median number of lesions (nodules and hyperplasia) was 3.0 for group 1, 2.0 for group 2 and 1.5-3 (p=0.052). When comparing only the presence or absence of lesion, there was a decrease in the number of lesions in group 3 as compared with group 1 (p=0.03) but not in relation to group 2. There were no metastases or other changes in other organs. The anaerobic physical activity, but not aerobic, diminishes the incidence of experimental lung tumors.

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EKGs may soon screen for cardiomyopathy, thanks to AI

An AI-based approach to diagnostics could see electrocardiograms repurposed to screen for hypertrophic cardiomyopathy in the not-so-distant future.

By Anicka SlachtaFebruary 20, 2020

An AI-based approach to diagnostics could see electrocardiograms (EKGs) repurposed to screen for hypertrophic cardiomyopathy in the not-so-distant future.

Mayo Clinic researchers reported in the Journal of the American College of Cardiology this month that they were able to train a convolutional neural network (CNN) to detect characteristics of hypertrophic cardiomyopathy that would have otherwise gone unseen by a physician. The approach retools the standard 12-lead EKG to act as a second pair of eyes in detecting the illness, which is thought to be underdiagnosed due to a lack of outward symptoms.

Senior author and Mayo Clinic cardiologist Peter Noseworthy, MD, co-first author Konstantinos Siontis, MD, and colleagues trained and validated a CNN using digital 12-lead EKG data from 2,448 patients known to have hypertrophic cardiomyopathy and 51,153 age- and sex-matched patients without the condition. They then tested the performance of the algorithm in a separate subset of 612 patients with hypertrophic cardiomyopathy and 12,788 controls.

The AI’s ability to differentiate patients with hypertrophic cardiomyopathy from those without it resulted in an area under the curve (AUC) of 0.96, the authors reported. Where an AUC of 0.5 is considered poor and an AUC of 1.0 is excellent, the result was good news.

“The good performance in patients with a normal EKG is fascinating,” Noseworthy said in a release. “It’s interesting to see that even a normal EKG can look abnormal to a convolutional neural network. This supports the concept that these networks find patterns that are hiding in plain sight.”

Subgroup testing revealed further successes; the AUC for predicting hypertrophic cardiomyopathy in people with concomitant left ventricular hypertrophy was 0.95, and the AUC in a subgroup of patients with only normal EKGs was also 0.95. The AUC for a subgroup of patients diagnosed with aortic stenosis was 0.94.

“The subgroups are important for understanding how to apply the test,” Siontis, a resident cardiologist at Mayo Clinic, said in the release. “It’s good to see that the AI performs well when the EKG is normal as well as when it is abnormal due to left ventricular hypertrophy. Perhaps even more important is the fact that the algorithm performed best in the younger subset of patients in our study (under 40 years old), which highlights its potential value in screening younger adults.”

Still, Siontis said a lot of work still needs to be done, including testing the AI in other populations and ages.

“This is a promising proof-of-concept, but I would caution that, despite its powerful performance, any screening test for a relatively uncommon condition is destined to have high false positive rates and low positive predictive value in a general population,” he said. “We still need to better understand which particular populations will benefit from this test as a screening tool.”

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FEBRUARY 12, 2020

Monitoring organs and cells in living fly larvae

by European Molecular Biology Laboratory

Monitoring organs and cells in living fly larvae
This image is a composition of snap shots from a time lapse video of a closing wound in the epidermis of a Drosophila larvae. The cells express two fluorescently labelled markers: a PIP3 sensor (green) and the myosin light chain (magenta). Credit: Parisa Kakanj/EMBL

Small changes in a cell’s composition can radically transform its function and drive the development of diseases like diabetes, cancer or neuronal dysfunction. Scientists led by the European Molecular Biology Laboratory in Heidelberg, the Institute for Genetics of the University of Cologne, the Max Planck Institute for Biology of Ageing, and CECAD and the CMMC in Cologne have developed a method to study processes taking place in the cells of a living fruit fly larva. This technique, published in Nature Protocols on 10 February, provides a simple but effective way to study the functions of organs in living animals.

For decades, scientists have been using the fruit fly Drosophila to understand biological processes. Key biological processes and 60% of fruit fly genes are also seen in humans, having been evolutionarily conserved. The fruit fly is therefore a powerful model organism for studying genetics. Scientists have created many genetic tools and techniques to study molecular processes of development and human disease in the fruit fly.

The challenge

Most previous studies have been carried out in the Drosophila embryo or in adult flies, but the fruit fly larva also offers enormous research potential. Its transparent body, with highly developed functional organs including brain, gut, and muscle, makes the larva an excellent system for observing the dynamics of cellular and molecular processes in living animals.

“The cells in a fruit fly larva are much bigger than in the embryo. You can see all organelles and even the subcellular processes. That’s the beauty of the system,” says Parisa Kakanj, the scientist who led the study in Germany.

However, the larva’s continuous crawling makes live monitoring a challenge, and some cellular processes only reveal their secrets through long-term imaging. Kakanj, a researcher in the groups of Maria Leptin and Linda Partridge, tackled this challenge and developed a method for simple immobilization of the larvae that allows long-term live imaging and the investigation of cellular events at high resolution.

Simple, fast, and efficient

In the past, scientists have used mechanical methods or anesthetics to tranquilize fruit fly larvae. Both approaches had undesired side-effects, such as mechanical pressure, limited immobilization, and high mortality. Further, simultaneous screening of many larvae was impossible.

“In contrast to previous techniques, we developed a simple method for short-term treatment with ether, a classical anesthetic. This approach allowed undisrupted long-term immobilization of many larvae in parallel,” explains Parisa Kakanj.

A promising model for drug discovery

To prove the technique’s capabilities, the team investigated wound healing in larvae. They examined the influence of insulin and TOR—crucial signaling molecules for cell survival, growth, and proliferation—on this process. By studying the subcellular dynamics, the scientists created a temporal map of insulin and TOR pathway activity during wound closure. They found that lowering insulin signaling at the wound edge slows down the healing process.

Long-term in vivo imaging, coupled with genetic manipulations, opens the path to many aspects of biology and physiology. “This technique will help many scientists studying neuronal signaling, fat metabolism, or tumor formation, and will provide new opportunities for drug discovery,” says Parisa Kakanj.

Explore furtherDiabetes: new hope for better wound healing

More information: Parisa Kakanj et al. Long-term in vivo imaging of Drosophila larvae, Nature Protocols (2020). DOI: 10.1038/s41596-019-0282-zJournal information:Nature ProtocolsProvided by European Molecular Biology Laboratory4 shares

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Scientists Have Held Individual Atoms for the Very First Time

It’s a quantum physics breakthrough. And it’s all thanks to some tweezers.


By Caroline DelbertFeb 21, 2020imageUNIVERSITY OF OTAGO

  • Researchers have held individual atoms and released them to interact for the first time.
  • Their secret weapon is a set of three optical tweezer setups to hold atoms in suspension.
  • They made predictions about the few-body problem, but were surprised by their results.

Scientists have trapped and observed individual atoms for what they say is the first time ever. The mechanism is a kind of supercooled atom rodeo, where individual atoms at nearly absolute zero are held in separate compartments before being released to interact in specific ways.

The researchers use optical tweezers as part of their setup. Atoms can be isolated and held in place with optical tweezers, and these researchers simultaneously used three separate tweezers. Once three atoms are held in laser lock, the researchers move all three setups together and then drop two of the gates. All three atoms are then free to interact in the remaining optical tweezer setup.

This process may sound simple, but it’s actually complex and fussy to do. It was worth it: “When three atoms interact, one possible outcome is that two of the atoms collide to form a molecule while the third gets a ‘kick’ of energy as a result,” Physics reports. “This process, known as three-body recombination, occurs everywhere from laboratory plasmas to star-forming gas clouds, but despite its ubiquity, it had yet to be directly observed.”

The researchers had fairly open-ended predictions for outcomes of this experiment, but they were still surprised by what happened. Atoms did act out the predicted three-body recombination, but they were much slower than the researchers predicted. They aren’t sure why this is, but they speculate that the tight confines in the optical tweezer setup has something to do with it. And other iterations showed that two atoms bonded without doing anything to the third, simply leaving it behind. (Sad trombones.)

Physics reports that the slow recombination rates are considered a promising and exciting outcome. The research team’s predictions were based on existing knowledge about three-body recombination and theoretical models of how it works up close. For results to go against those predictions, it shows that something more interesting is at play than what scientists currently understand.RELATED STORIESArtificial Atoms May Lead to Quantum BreakthroughA Quantum Leap in the Classical WorldThe 7 Discoveries That Won the Breakthrough Prize

This is one reason why sophisticated nano-observation and manipulation are so important. Experimental quantum mechanics has been something of a black box due to the sheer difficulty of managing to look at anything that was happening. “The introduction of optical tweezers for trapping atoms has opened remarkable opportunities for manipulating few-body systems,” the researchers explain in their abstract.

Few-body problems are no relation to the three-body problem, beyond the fact that both have, well, a few things. Or are they related? In quantum mechanics, more than three interacting particles of certain kinds end up behaving in ways that are unpredictable and insoluble using “traditional” (for quantum mechanics) methods.

Springer’s wide-ranging Few-Body Systems journal defines it this way:

“Examples of few-body problems include light nuclear systems (few-nucleon bound and scattering states), small molecules as well as light atoms (few-electron systems in external fields), specific systems in condensed matter and surface physics (quantum dots); however, also systems as large as celestial systems and as small as elementary particles.”

That’s a real twist there at the end.

Optical tweezers are just one of the ways scientists are getting up close and personal with individual particles for the first time, and supercooled environments allow for a variety of manipulations that previous generations couldn’t have dreamed of. Now, the tools to explain a delayed three-body recombination could be within our grasp—or within an atom’s grasp.MORE FROMSCIENCE10 Amazing Facts About Polar BearsCorny Batteries Could Hold Quadruple the ChargeA Very Tiny Nuclear Plant Is Coming to IdahoHero Cat Receives Four 3D-Printed Titanium LimbsAll Coral Reefs Could Be Dead Within 80 YearsWhat Would Happen If Planes Flew 2,000 Feet HigherA Closer Look at Lake Michigan’s Ice VolcanoesThe Big Math Errors in the Iowa Caucus DataWere Dinosaurs Warm Blooded?How a Rotating Detonation Engine Works

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Crystal-stacking process can produce new materials for high-tech devices

February 5, 2020 By Renee Meiller For news media 

The magnetic, conductive and optical properties of complex oxides make them key to components of next-generation electronics used for data storage, sensing, energy technologies, biomedical devices and many other applications.

Stacking ultrathin complex oxide single-crystal layers — those composed of geometrically arranged atoms — allows researchers to create new structures with hybrid properties and multiple functions. Now, using a new platform developed by engineers at the University of Wisconsin–Madison and the Massachusetts Institute of Technology, researchers will be able to make these stacked-crystal materials in virtually unlimited combinations.

The team published details of its advance Feb. 5 in the journal Nature.

To grow layers of single-crystal oxides for electronic components requires neighboring layers to interlock like Lego blocks. A new method throws out that limitation, producing new capabilities for data storage, sensing, energy technologies, biomedical devices and many other applications. COURTESY OF CHANG-BEOM EOM

Epitaxy is the process for depositing one material on top of another in an orderly way. The researchers’ new layering method overcomes a major challenge in conventional epitaxy — that each new complex oxide layer must be closely compatible with the atomic structure of the underlying layer. It’s sort of like stacking Lego blocks: The holes on the bottom of one block must align with the raised dots atop the other. If there’s a mismatch, the blocks won’t fit together properly.

“The advantage of the conventional method is that you can grow a perfect single crystal on top of a substrate, but you have a limitation,” says Chang-Beom Eom, a UW–Madison professor of materials science and engineering and physics. “When you grow the next material, your structure has to be the same and your atomic spacing must be similar. That’s a constraint, and beyond that constraint, it doesn’t grow well.”

A couple of years ago, a team of MIT researchers developed an alternate approach. Led by Jeehwan Kim, an associate professor in mechanical engineering and materials science and engineering at MIT, the group added an ultrathin intermediate layer of a unique carbon material called graphene, then used epitaxy to grow a thin semiconducting material layer atop that. Just one molecule thick, the graphene acts like a peel-away backing due to its weak bonding. The researchers could remove the semiconductor layer from the graphene. What remained was a freestanding ultrathin sheet of semiconducting material.

Eom, an expert in complex oxide materials, says they are intriguing because they have a wide range of tunable properties — including multiple properties in one material — that many other materials do not. So, it made sense to apply the peel-away technique to complex oxides, which are much more challenging to grow and integrate.

Chang-Beom Eom

“If you have this kind of cut-and-paste growth and removal, combined with the different functionality of putting single-crystal oxide materials together, you have a tremendous possibility for making devices and doing science,” says Eom, who connected with mechanical engineers at MIT during a sabbatical there in 2014.

The Eom and Kim research groups combined their expertise to create ultrathin complex oxide single-crystal layers, again using graphene as the peel-away intermediate. More importantly, however, they conquered a previously insurmountable obstacle — the difference in crystal structure — in integrating different complex oxide materials.

“Magnetic materials have one crystal structure, while piezoelectric materials have another,” says Eom. “So you cannot grow them on top of each other. When you try to grow them, it just becomes messy. Now we can grow the layers separately, peel them off, and integrate them.”

In its research, the team demonstrated the efficacy of the technique using materials such as perovskite, spinel and garnet, among several others. They also can stack single complex oxide materials and semiconductors.

“This opens up the possibility for the study of new science, which has never been possible in the past because we could not grow it,” says Eom. “Stacking these was impossible, but now it is possible to imagine infinite combinations of materials. Now we can put them together.”

The advance also opens doors to new materials with functionalities that drive future technologies.

“This advance, which would have been impossible using conventional thin film growth techniques, clears the way for nearly limitless possibilities in materials design,” says Evan Runnerstrom, program manager in materials design in the Army Research Office, which funded part of the research. “The ability to create perfect interfaces while coupling disparate classes of complex materials may enable entirely new behaviors and tunable properties, which could potentially be leveraged for new Army capabilities in communications, reconfigurable sensors, low power electronics, and quantum information science.”


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Powerful antibiotic discovered using machine learning for first time

Team at MIT says halicin kills some of the world’s most dangerous strains

Ian Sample Science editor @iansample

Thu 20 Feb 2020 16.28 GMTFirst published on Thu 20 Feb 2020 16.13 GMT


The culture plate on the right has bacteria that is resistant to all of the antibiotics tested
 The culture plate on the right has bacteria that is resistant to all of the antibiotics tested. Photograph: Science History Images/Alamy

A powerful antibiotic that kills some of the most dangerous drug-resistant bacteria in the world has been discovered using artificial intelligence.

The drug works in a different way to existing antibacterials and is the first of its kind to be found by setting AI loose on vast digital libraries of pharmaceutical compounds.

Tests showed that the drug wiped out a range of antibiotic-resistant strains of bacteria, including Acinetobacter baumannii and Enterobacteriaceae, two of the three high-priority pathogens that the World Health Organization ranks as “critical” for new antibiotics to target.

“In terms of antibiotic discovery, this is absolutely a first,” said Regina Barzilay, a senior researcher on the project and specialist in machine learning at Massachusetts Institute of Technology (MIT).

“I think this is one of the more powerful antibiotics that has been discovered to date,” added James Collins, a bioengineer on the team at MIT. “It has remarkable activity against a broad range of antibiotic-resistant pathogens.”

Lack of antibiotics in low income countries ‘worsening superbugs threat’

 Read more

Antibiotic resistance arises when bacteria mutate and evolve to sidestep the mechanisms that antimicrobial drugs use to kill them. Without new antibiotics to tackle resistance, 10 million lives around the world could be at risk each year from infections by 2050, the Cameron government’s O’Neill report warned.

To find new antibiotics, the researchers first trained a “deep learning” algorithm to identify the sorts of molecules that kill bacteria. To do this, they fed the program information on the atomic and molecular features of nearly 2,500 drugs and natural compounds, and how well or not the substance blocked the growth of the bug E coli.

Once the algorithm had learned what molecular features made for good antibiotics, the scientists set it working on a library of more than 6,000 compounds under investigation for treating various human diseases. Rather than looking for any potential antimicrobials, the algorithm focused on compounds that looked effective but unlike existing antibiotics. This boosted the chances that the drugs would work in radical new ways that bugs had yet to develop resistance to.

Jonathan Stokes, the first author of the study, said it took a matter of hours for the algorithm to assess the compounds and come up with some promising antibiotics. One, which the researchers named “halicin” after Hal, the astronaut-bothering AI in the film 2001: A Space Odyssey, looked particularly potent.

Writing in the journal Cell, the researchers describe how they treated numerous drug-resistant infections with halicin, a compound that was originally developed to treat diabetes, but which fell by the wayside before it reached the clinic.

Tests on bacteria collected from patients showed that halicin killed Mycobacterium tuberculosis, the bug that causes TB, and strains of Enterobacteriaceae that are resistant to carbapenems, a group of antibiotics that are considered the last resort for such infections. Halicin also cleared C difficile and multidrug-resistant Acinetobacter baumannii infections in mice.

To hunt for more new drugs, the team next turned to a massive digital database of about 1.5bn compounds. They set the algorithm working on 107m of these. Three days later, the program returned a shortlist of 23 potential antibiotics, of which two appear to be particularly potent. The scientists now intend to search more of the database.

Stokes said it would have been impossible to screen all 107m compounds by the conventional route of obtaining or making the substances and then testing them in the lab. “Being able to perform these experiments in the computer dramatically reduces the time and cost to look at these compounds,” he said.

Barzilay now wants to use the algorithm to find antibiotics that are more selective in the bacteria they kill. This would mean that taking the antibiotic kills only the bugs causing an infection, and not all the healthy bacteria that live in the gut. More ambitiously, the scientists aim to use the algorithm to design potent new antibiotics from scratch.

“The work really is remarkable,” said Jacob Durrant, who works on computer-aided drug design at the University of Pittsburgh. “Their approach highlights the power of computer-aided drug discovery. It would be impossible to physically test over 100m compounds for antibiotic activity.”

“Given typical drug-development costs, in terms of both time and money, any method that can speed early-stage drug discovery has the potential to make a big impact,” he added.

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Einstein’s Lost Theory Describes a Universe Without a Big Bang

The CruxBy Amir AczelMarch 7, 2014 1:32 PM


Einstein with Edwin Hubble, in 1931, at the Mount Wilson Observatory in California, looking through the lens of the 100-inch telescope through which Hubble discovered the expansion of the universe in 1929. Courtesy of the Archives, Calif Inst of Technology.


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In 1917, a year after Albert Einstein’s general theory of relativity was published—but still two years before he would become the international celebrity we know—Einstein chose to tackle the entire universe. For anyone else, this might seem an exceedingly ambitious task—but this was Einstein.

Einstein began by applying his field equations of gravitation to what he considered to be the entire universe. The field equations were the mathematical essence of his general theory of relativity, which extended Newton’s theory of gravity to realms where speeds approach that of light and masses are very large. But his math was better than he wanted to believe—his equations told him that the universe could not stay static: it had to either expand or contract. Einstein chose to ignore what his mathematics was telling him.

The story of Einstein’s solution to this problem—the maligned “cosmological constant” (also called lambda)—is well known in the history of science. But this story, it turns out, has a different ending than everyone thought: Einstein late in life returned to considering his disgraced lambda. And his conversion foretold lambda’s use in an unexpected new setting, with immense relevance to a key conundrum in modern physics and cosmology: dark energy.

The Static Universe Before Hubble

Einstein had what would have seemed a very good reason for ignoring what the math was telling him. Few people know that Einstein was not merely a superb theoretician, but also a physicist skilled in observations and experiments. In 1914, Einstein was wooing a young Scottish-German astronomer, Erwin Finlay Freundlich, to seek proof of relativity through shifts in apparent star locations during a total solar eclipse that was to take place in the Crimea (which ended badly because of the outbreak of World War I). Letters that Einstein wrote to Freundlich during 1913-4 reveal that Einstein had a burgeoning interest in astronomy and understood much about the field, including technical details of lenses and mirrors.* Ironically, his deep knowledge of astronomy would lead Einstein to make the greatest blunder of his entire career….Or not.

Astronomical knowledge of the time told Einstein that the universe was unchanging in its size. How could someone think that? Well, this was the second decade of the twentieth century, and telescopes were still relatively small and not very powerful. They were strong enough to allow astronomers to discover all the now-known planets in our solar system, to get good views of “cloudy patches” of the sky such as the Orion nebula, and to view several galaxies, including the Great Andromeda Galaxy—our nearest neighbor at 2.3 million light years’ distance.

But astronomers believed that all these fuzzy objects they were seeing were somehow part of our own Milky Way. (The great Eddington even believed at that time that the Sun was the center of this universe! And an idea about the distances to the most faraway stars only began to emerge through the work of Harlow Shapely on Cepheid variables, conducted at the Mount Wilson Observatory, in 1916.) Since astronomers could detect no expansion of stars or nebulas in the entire cosmos known to them, they assumed that the universe was static.

The Birth of the Cosmological Constant

To force his equations—which theoretically predicted the expansion of the universe—to remain still, Einstein invented the cosmological constant, λ. He multiplied the metric tensor in his equation, g, by the cosmological constant, leading to a term λg, which adjusted his metric tensor acting on space-time. This mathematical trick assured him that his equations would yield a universe that was prevented from expanding or contracting.

Unbeknownst to Einstein, at exactly the time he published his paper on the cosmological equations, across the world in California, the new 100-inch Hooker telescope was being fit in its place at the Mount Wilson Observatory. Within a little over a decade, Edwin Hubble, aided by Vesto Slipher and Milton Humason, would use this, the most powerful telescope on Earth, to study the redshift of distant galaxies and conclude from it definitively that our universe is expanding.

Einstein heard about these results, and in the early 1930s, he traveled to California and met with Hubble.  At the Mount Wilson Observatory he saw the massive data set on distant galaxies that had led to “Hubble’s law” describing the expansion of the universe and got angry at himself: had he not forced his equations to stay static with that cosmological-constant invention of his, he could have theoretically predicted Hubble’s findings! That would have been worth a second Nobel Prize for him (he deserved a few more, anyway)—in the same way, for example, that the CERN scientists’ 2012 experimental discovery of the Higgs boson recently won Peter Higgs the Nobel in 2013. In disgust, Einstein exclaimed after his Mount Wilson visit: “If there is no quasi-static world, then away with the cosmological term!” and never considered the cosmological constant again. Or so we thought until recently.

Dark Energy: Lambda Returns

When a genius such as Einstein makes a mistake, it tends to be a “good mistake.” (I am indebted to the mathematician Goro Shimura for this expression.) It can’t simply go away—there is too much thought that has gone into it. So, like a phoenix, Einstein’s cosmological constant made a remarkable comeback, very unexpectedly, in 1998.

That year, two groups of astronomers made an announcement that rocked the world of science. The “Supernova Cosmology Project,” based in California and headed by Saul Perlmutter, and the “High-Z SN Search” group at Harvard-Smithsonian and Australia, announced their results of the shifts of distant galaxies leading to a conclusion that nobody had expected: The universe, rather than slowing its expansion since the Big Bang, is actually accelerating its expansion!

And it turns out that the best theoretical way to explain the accelerating universe is to revive Einstein’s discarded lambda. The cosmological constant (acting differently from how it was designed, as a force stopping the expansion) is the best explanation we have for the mysterious “dark energy” seen to permeate space and push the universe ever outward at an accelerating rate. To most physicists today, lambda, cosmological constant, and dark energy are closely synonymous. But unfortunately Einstein was not there to witness the reversal of his “greatest blunder,” having died in 1955.

And it has been widely assumed that he died without ever reconsidering the cosmological constant. Until now.

Einstein’s Lost Manuscript

The Irish physicist Cormac O’Raifeartaigh was perusing documents at the Einstein Archives at the Hebrew University in Jerusalem in late 2013 when he discovered a handwritten manuscript by Einstein that scholars had never looked at carefully before. The paper, called “Zum kosmologischen Problem” (“About the Cosmological Problem”), had been erroneously filed as a draft of another paper, which Einstein published in 1931 in the annals of the Prussian Academy of Sciences. But it was not. It seems that even with Einstein, old notions die hard: This paper was his stubborn attempt to resurrect the cosmological constant he had vowed never to use again.

In a paper just filed on the electronic physics repository ArXiv, O’Raifeartaigh and colleagues show that in the early 1930s (the assumed date is 1931, but this is uncertain), Einstein was still trying to return to his 1917 analysis of a universe with a cosmological constant. Einstein wrote (the authors’ translation from the German):

“This difficulty [the inconsistency of the laws of gravity with a finite mean density of matter] also arises in the general theory of relativity. However, I have shown that this can be overcome through the introduction of the so-called “λ–term” to the field equations… I showed that these equations can be satisfied by a spherical space of constant radius over time, in which matter has a density ρ that is constant over space and time.”

But he was now aware of Hubble’s discovery of the expansion of the universe:

“On the other hand, Hubbel’s [sic**] exceedingly important investigations have shown that the extragalactic nebulae have the following two properties 1) Within the bounds of observational accuracy they are uniformly distributed in space 2) They possess a Doppler effect proportional to their distance”  (Quoted in O’Raifeartaigh, et al., 2014, p. 4)

And so Einstein proposed a revision of his model, still with a cosmological constant, but now the constant was responsible for the creation of new matter as the universe expanded (because Einstein believed that in an expanding universe, the overall density of matter had to still stay constant):

In what follows, I would like to draw attention to a solution to equation (1) that can account for Hubbel’s facts, and in which the density is constant over time.” And: “If one considers a physically bounded volume, particles of matter will be continually leaving it. For the density to remain constant, new particles of matter must be continually formed in the volume from space.”

Einstein achieves this property by the use of his old cosmological constant, λ:

“The conservation law is preserved in that by setting the λ-term, space itself is not empty of energy; as is well-known its validity is guaranteed by equations (1).”  (Quoted in O’Raifeartaigh, et al., 2014, p. 7.)

So Einstein keeps on using his discarded lambda—despite the fact that he invented it for a non-expanding universe. If the universe expands as Hubble showed, Einstein seems to be saying, then I still need my lambda—now to keep the universe from becoming less dense as it expands in volume.

Almost two decades later, a similar “steady state” universe would be proposed by Fred Hoyle, Hermann Bondi, and Tommy Gold, in papers  published in 1949. But these models of the universe are not supported by modern theories. In fact, a tenet of modern cosmology is that as the universe will expand a great deal (after an unimaginably long period of time), it will become very thinly populated, rather than dense, with stray photons and electrons zipping alone through immense expanses of emptiness, all stars having by then died and disappeared.

Views of the Cosmos, Old and New

As for why Einstein was so intent on maintaining the use of his discarded lambda, the constant represents the energy of empty space—a powerful notion—and Einstein in this paper wanted to use this energy to create new particles as time goes on.

Today we view the same energy of the vacuum as the reason for the acceleration of the universe’s expansion. Einstein presciently understood that the energy of the vacuum, unleashed by his cosmological constant, was too important to let die.

Einstein was far from the only person to wonder about the universe and whether it has always existed or was born at some point in the past and would die at a future time. This question has been pondered by people ever since the dawn of civilization. The origin and ultimate fate of the universe are highly interlinked with its overall geometry—the actual shape of the space-time manifold. In a closed geometry, the universe was born and will someday recollapse on itself. In an open geometry, it was born and will expand forever, and the same happens in a flat (Euclidean) geometry. Based on modern theories supported by satellite observations of the microwave background radiation in space, space-time is nearly perfectly Euclidean, meaning that the universe was born in a Big Bang and will expand forever, becoming less dense with time. Eventually, matter may decay into few kinds of elementary particles and photons, the distances among them growing to infinity.

Cosmology in Context

Between 1917 and 1929—the year Hubble and his colleagues discovered the expansion of the universe, implying the possibility of a beginning for the cosmos—Einstein and most scientists held that the universe was “simply there” with no beginning or end. But it’s interesting to note that creation myths across cultures tell the opposite story. Traditions of Chinese, Indian, pre-Colombian, and African cultures, as well as the biblical book of Genesis, all describe (clearly in allegorical terms) a distinct beginning to the universe—whether it’s the “creation in six days” of Genesis or the “Cosmic Egg” of the ancient Indian text the Rig Veda.

This is an interesting example of scientists being dead wrong (for a time) and primitive ancient observers having an essentially correct intuition about nature. And with the present explosion of models of the universe and sometimes outrageous “scientific speculations” about its origin and future, some commentators are clearly overstating what science has done. One recent example is the book by the physicist Lawrence M. Krauss, A Universe From Nothing, which claims that science has shown that the universe somehow sprang out of sheer nothingness.***

A century ago, Einstein’s powerful field equations of gravitation showed the way forward. His uncanny intuition about the universe prevailed despite temporary reversals, and his decades-old insights are now at the cutting edge of modern physics and cosmology, helping us shed light on the greatest mysteries of all: the nature of matter, gravity, time, space, and the mysterious dark energy pushing it all outwards.


*I was fortunate to be the first scholar to examine these letters before they became accessible to the public, translated them from the German with the help of my father, and published some of the results.

**It’s interesting that Einstein repeatedly misspells the name of Edwin Hubble (“Hubbel”). Had he not yet met Hubble in person? We don’t know. The spelling error does hint at the fact that Hubble’s discovery was not yet so strongly established that his name would be well known by all scientists.

***I take strong issue with this approach, and expand on the topic of what is known by science about the birth and fate of the universe, in a forthcoming book.


Does the Universe Need Dark Matter to Form Galaxies? A Controversial Model Says ‘No’The Remarkable Legacy of Spitzer—the Telescope and the ManSome Scientists Are Skeptical Dark Energy Even Exists — But Others Push Back


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A Community-Based Intervention for Managing Hypertension in Rural South Asia

List of authors.

  • Tazeen H. Jafar, M.D., M.P.H., 
  • Mihir Gandhi, Ph.D., 
  • H. Asita de Silva, D.Phil., F.R.C.P., 
  • Imtiaz Jehan, F.C.P.S., 
  • Aliya Naheed, M.B., B.S., Ph.D., 
  • Eric A. Finkelstein, Ph.D., 
  • Elizabeth L. Turner, Ph.D., 
  • Donald Morisky, Sc.D., 
  • Anuradhani Kasturiratne, M.B., B.S., M.D., 
  • Aamir H. Khan, F.C.P.S., 
  • John D. Clemens, Ph.D., 
  • Shah Ebrahim, D.M., 
  • et al.,
  •  for the COBRA-BPS Study Group*




The burden of hypertension is escalating, and control rates are poor in low- and middle-income countries. Cardiovascular mortality is high in rural areas.


We conducted a cluster-randomized, controlled trial in rural districts in Bangladesh, Pakistan, and Sri Lanka. A total of 30 communities were randomly assigned to either a multicomponent intervention (intervention group) or usual care (control group). The intervention involved home visits by trained government community health workers for blood-pressure monitoring and counseling, training of physicians, and care coordination in the public sector. A total of 2645 adults with hypertension were enrolled. The primary outcome was reduction in systolic blood pressure at 24 months. Follow-up at 24 months was completed for more than 90% of the participants.


At baseline, the mean systolic blood pressure was 146.7 mm Hg in the intervention group and 144.7 mm Hg in the control group. At 24 months, the mean systolic blood pressure fell by 9.0 mm Hg in the intervention group and by 3.9 mm Hg in the control group; the mean reduction was 5.2 mm Hg greater with the intervention (95% confidence interval [CI], 3.2 to 7.1; P<0.001). The mean reduction in diastolic blood pressure was 2.8 mm Hg greater in the intervention group than in the control group (95% CI, 1.7 to 3.9). Blood-pressure control (<140/90 mm Hg) was achieved in 53.2% of the participants in the intervention group, as compared with 43.7% of those in the control group (relative risk, 1.22; 95% CI, 1.10 to 1.35). All-cause mortality was 2.9% in the intervention group and 4.3% in the control group.


In rural communities in Bangladesh, Pakistan, and Sri Lanka, a multicomponent intervention that was centered on proactive home visits by trained government community health workers who were linked with existing public health care infrastructure led to a greater reduction in blood pressure than usual care among adults with hypertension. (Funded by the Joint Global Health Trials scheme; COBRA-BPS ClinicalTrials.gov number, NCT02657746. opens in new tab.)

Uncontrolled high blood pressure is the leading attributable risk factor for death globally.1 Treatment of hypertension reduces risk, but less than one third of persons with hypertension have controlled blood pressure.2-4 Asians have enhanced susceptibility to vascular disease.5-7 Uncontrolled blood pressure is particularly prevalent in rural areas in low- and middle-income countries where health literacy and health systems are weakest and case fatality rates for cardiovascular disease are highest.8,9

Our previous trial in urban Pakistan suggested that a combined intervention of home health education delivered by community health workers, coupled with training of physicians, lowered blood pressure and was cost-effective.10,11 However, the trial intervention used a privately contracted health care workforce, which was not integrated into the existing community infrastructure, and would not be sustainable or scalable. More than 30 trials on hypertension management in low- and middle-income countries have similar limitations.12,13

We conducted a cluster-randomized, controlled trial (Control of Blood Pressure and Risk Attenuation–Bangladesh, Pakistan, and Sri Lanka [COBRA-BPS]) in rural communities in three South Asian countries over a period of 2 years to evaluate the effectiveness of a scalable, multicomponent intervention designed specifically for hypertension management in rural areas.14 The intervention was conceptually based on our previous intervention in urban Pakistan and was modified for delivery in rural settings in the three South Asian countries.10,15Additional components were added (blood-pressure monitoring by government community health workers, checklists, care coordinators, and compensation for additional services) in response to the results of a feasibility study.10,14,15 We hypothesized that a low-cost, multicomponent intervention integrated into the existing public health system would be more effective than usual care in lowering blood pressure among adults with hypertension in rural communities.



The trial was a multicountry, cluster-randomized, controlled trial in 30 rural villages (communities) of the districts Tangail and Munshiganj in Bangladesh, Thatta in Pakistan, and Puttalam in Sri Lanka. Because the intervention was delivered through the health systems in the rural areas of these countries, a cluster-randomized, controlled trial design was chosen to minimize contamination (i.e., to prevent participants in the control group from actively or passively receiving some or all of the multicomponent intervention). The trial protocol and statistical analysis plan were published previously14,16 and are available with the full text of this article at NEJM.org. The authors vouch for the completeness and accuracy of the data and for the fidelity of the trial to the protocol. The ethics review committee at each participating institution approved the trial. All the participants provided written informed consent before screening. The conduct of the trial was independently reviewed by the trial steering committee and the data and safety monitoring committee. The funders had no role in the design, conduct, analysis, or reporting of the trial.


The main eligibility criteria were an age of 40 years or older and hypertension, defined as current use of antihypertensive medications or persistently elevated blood pressure (systolic blood pressure ≥140 mm Hg or diastolic blood pressure ≥90 mm Hg) based on each set of the last two of three measurements from 2 separate days. Pregnant women and persons with advanced illness (e.g., those receiving dialysis or with liver failure), terminal illness, or an inability to travel to the clinic were excluded. (Additional details are provided in the protocol.)


The unit of randomization was a cluster of 250 to 300 households served by one or two community health workers and one government clinic.14,16 A total of 30 clusters were randomly selected from designated districts in the three countries (10 per country). Randomization was stratified according to country and distance from the government clinic (near [≤2 km] or far [>2 km]), and clusters were assigned in a 1:1 ratio to either the multicomponent intervention (intervention group) or usual care (control group) with the use of a computer-generated program (Table S1 in the Supplementary Appendix, available at NEJM.org).


Multicomponent Intervention

The details of the intervention components are described in the trial protocol; a condensed description is provided here. The first component was blood-pressure monitoring and the use of checklists to guide monitoring and referral to physicians. Government community health workers were trained in measuring blood pressure with the use of a digital blood-pressure monitor. They monitored participants’ blood pressures at home visits every 3 months. On the basis of a checklist (see the Supplementary Appendix), participants with very poorly controlled blood pressure (systolic blood pressure ≥160 mm Hg or diastolic blood pressure ≥100 mm Hg) or those at high risk for cardiovascular disease were referred to a physician at the government primary care facility.

The second component was home health education by government community health workers. Community health workers were trained in a curriculum regarding home health education and in strategies regarding behavior-change communication over a period of 5 days (see the Supplementary Appendix), followed by retraining in 2 months and then annually. Details of the training curricula are provided in the protocol. Home health education was delivered to all the participants and their family members at home visits every 3 months. All the participants were encouraged to adhere to antihypertensive medications and to follow up with their physicians. A checklist was completed by the community health workers and submitted to their supervisors.

The third component was training of physicians in blood-pressure monitoring, management of hypertension, and use of the checklist. A treatment algorithm was based on the Joint National Committee and 2013 European Society of Cardiology guidelines.17 Generic antihypertensive medications (thiazide-like diuretics, angiotensin-converting–enzyme inhibitors or angiotensin-receptor blockers, and calcium-channel blockers) and statins (for patients at high risk for cardiovascular disease) were used as indicated.17,18 The target blood pressure was a systolic blood pressure of less than 140 mm Hg and a diastolic blood pressure of less than 90 mm Hg (see the treatment algorithm in the Supplementary Appendix). Physicians were retrained in 2 months and annually thereafter.

The fourth component was a designated hypertension triage reception desk and hypertension care coordinator at the government clinics. A hypertension triage reception desk to reduce waiting time was established at the intervention clinics. A hypertension care coordinator was appointed to track participants with very poorly controlled blood pressure.

The fifth component was compensation for additional health services and targeted subsidies. Compensation was paid to the community health workers at the discretion of the local district health office. The cost of medications and diagnostics was borne primarily by the patients in Bangladesh and Pakistan and by publicly funded clinics in Sri Lanka, in accordance with the local norms.

Usual Care

Usual care consisted of existing services in the community, with routine home visits by community health workers for maternal and child care only. The clinics did not have designated triage reception desks or care coordinators for hypertension.


Trained research staff who were unaware of randomization status visited all households and invited adults 40 years of age or older to participate. Written informed consent was obtained before assessment for trial eligibility. Blood pressure was measured with an Omron HEM-7300 automatic digital monitor (Omron Healthcare) with the person in a sitting position according to the standard protocol.19 Three blood-pressure readings were taken consecutively 3 minutes apart with the use of a cuff of the appropriate size. Persons with consistently elevated blood pressure (systolic blood pressure ≥140 mm Hg or diastolic blood pressure ≥90 mm Hg based on the last two of three readings) were visited again after 2 weeks for remeasurement. Those with persistently elevated blood pressure at the second screening visit were invited for enrollment. Persons who were using antihypertensive medications were also invited to enroll.

Information on sociodemographic characteristics, health-seeking behavior, and associated costs was collected. Adherence to antihypertensive medications and statins was assessed by means of the Morisky Medication Adherence Scale (MMAS-8; scores range from 0 to 8, with higher scores indicating better adherence).20-22 Body-mass index (BMI) and waist circumference were measured.

All persons in both the intervention group and the control group with uncontrolled hypertension (systolic blood pressure ≥140 mm Hg or diastolic blood pressure ≥90 mm Hg) were asked by the research staff to consult their local physicians. Persons with very high blood pressure (systolic blood pressure ≥180 mm Hg or diastolic blood pressure ≥120 mm Hg) or those with acute associated symptoms (e.g., chest pain or breathlessness) were referred urgently to the district hospital.

Follow-up assessments of blood pressure were conducted at home visits every 6 months in both the intervention group and the control group. Adverse events including falls, hypotension, coronary heart disease, stroke, and heart failure were reported. Hospitalizations and deaths were tracked extensively (details are provided in the protocol). Fasting blood and random urine samples were collected at baseline and 24-month visits.


The prespecified primary outcome was the mean change in systolic blood pressure from baseline to 24 months. The mean of the second and third blood-pressure readings was used for all analyses, and the first was discarded.

Prespecified secondary outcomes included diastolic blood pressure, the percentage of participants with blood-pressure control (systolic blood pressure <140 mm Hg and diastolic blood pressure <90 mm Hg), blood-pressure response (blood-pressure control or decline in systolic blood pressure by 5 mm Hg), very poorly controlled blood pressure (systolic blood pressure ≥160 mm Hg or diastolic blood pressure ≥100 mm Hg), use of and mean MMAS-8 scores for adherence to antihypertensive medications and statins, and participant-reported health status according to the mean score on the visual-analogue scale of the EuroQol 5-Dimension 5-Level questionnaire (EQ-5D-5L; range, 0 to 100, with higher scores indicating better health) and the mean score on the EQ-5D-5L utility index calculated with the use of the Indonesian value set (range, −0.865 to 1, with higher scores indicating better health).23

Other prespecified secondary outcomes were BMI, waist circumference, physical activity, smoking status, intake of fruits and vegetables, dietary sodium intake (urinary sodium excretion), laboratory measures (plasma glucose level, lipid levels, estimated glomerular filtration rate, and urinary albumin-to-creatinine ratio), adverse events, new-onset diabetes, death from any cause, and hospitalizations for cardiovascular disease. Because information on secondhand smoking was missing at baseline, the prespecified measure of the INTERHEART score for the risk of cardiovascular disease was replaced with the Framingham score for the 10-year risk of cardiovascular disease.24 Although not prespecified, the daily dose of antihypertensive medications and the causes of death were evaluated. A prespecified cost-effectiveness analysis14 is being conducted, but costs of the intervention are reported below.


The estimated sample size was 2550 participants, under the assumptions of 85 participants per cluster, 10 clusters per country, an intraclass correlation coefficient of 0.02,10,15 80% retention, and a two-sided type I error rate of 5%. The trial had more than 99% power to detect a difference of 5 mm Hg in the change in systolic blood pressure between the two groups at 24 months.16

All analyses were performed with the use of the intention-to-treat principle. As prespecified in the statistical analysis plan, for the primary outcome analysis, the changes from baseline measurements were modeled with the use of a generalized linear mixed-effects model for repeated measures based on a participant-level analysis.25 The primary outcome model included fixed effects for baseline systolic blood pressure, country, distance of the cluster from the clinic, age, sex, trial group, time, and the interaction of trial group with time. No imputation technique was used because the analysis model accounts for missing data and is valid under the missing-at-random assumption. Similar analyses were used for secondary outcomes.25 We also conducted post hoc sensitivity and exploratory analyses, as explained in the Supplementary Appendix.

The incremental cost of intervention delivery was prospectively estimated for each country with the use of an activity-based costing approach that quantified all nonrecurring labor, rental space, materials, supplies, and services required to deliver the intervention. Further details are presented in the Supplementary Appendix.



Table 1.Baseline Characteristics of the Participants.

Of 11,510 persons who were screened for the trial, 2645 (23.0%) were enrolled from April 2016 through February 2017, with follow-up ending in March 2019. The 24-month follow-up ended with retention of 92.1% of the participants in the intervention group and 89.3% of those in the control group (Figs. S1 through S4). The baseline characteristics were generally balanced between the intervention group and the control group. The mean (±SD) age of the participants was 58.8±11.5 years, 64.3% were women, 25.8% had diabetes, and 41.9% had chronic kidney disease. Blood pressure was uncontrolled in 69.6% of the participants and very poorly controlled in 29.6% (Table 1 and Table S2).


In the intervention clusters during 2 years, 92.5% of the planned home health education checklists were completed; 91.5% of the participants received at least 80% of planned home visits (up to eight visits every 3 months over a period of 24 months) by community health workers for blood-pressure monitoring and home health education; and 76.8% of physician management checklists were completed for participants referred to clinics (Table S3).


Figure 1.Mean Change in Systolic Blood Pressure and Diastolic Blood Pressure over Time.Table 2.Intervention Effect on Blood-Pressure Outcomes and Use of Antihypertensive Medications.

At baseline, the mean systolic blood pressure was 146.7±22.4 mm Hg in the intervention group and 144.7±21.0 mm Hg in the control group. At 24 months, the mean systolic blood pressure fell by 9.0 mm Hg (95% confidence interval [CI], 7.7 to 10.4) in the intervention group and by 3.9 mm Hg (95% CI, 2.5 to 5.3) in the control group. The mean reduction in systolic blood pressure was 5.2 mm Hg greater in the intervention group than in the control group (95% CI, 3.2 to 7.1; P<0.001). The between-group differences in systolic blood pressure increased over time (Figure 1A and Table 2).

At baseline, the mean diastolic blood pressure was 89.1±14.7 mm Hg in the intervention group and 87.8±13.8 mm Hg in the control group. From baseline to 24 months, the mean reduction in diastolic blood pressure was 2.8 mm Hg greater in the intervention group than in the control group (95% CI, 1.7 to 3.9) (Table 2). Controlled blood pressure was achieved in 53.2% of the participants in the intervention group, as compared with 43.7% in the control group (relative risk, 1.22; 95% CI, 1.10 to 1.35) (Table 2).


At 24 months, the mean number of antihypertensive medications per participant increased more in the intervention group than in the control group (mean difference, 0.11) (Table 2), and the mean increase in the daily dose was greater by 6.3 mg (95% CI, 2.7 to 9.8). The mean MMAS-8 score for adherence to antihypertensive medications increased more in the intervention group than in the control group (mean difference, 0.60; 95% CI, 0.24 to 0.96). (Detailed results regarding adherence to antihypertensive medications and other secondary outcomes are provided in Table S4.)


Participants in the intervention group reported better overall health status than those in the control group: the mean increase in the score on the EQ-5D-5L visual-analogue scale was greater by 2.41 with the intervention (95% CI, 0.15 to 4.66). Similar results were observed for the EQ-5D-5L utility index. The mean MMAS-8 score for adherence to statins increased more in the intervention group than in the control group (mean difference, 0.42; 95% CI, 0.15 to 0.68).


There was no intervention-related serious adverse event in either group. All-cause mortality was 2.9% (39 deaths) in the intervention group and 4.3% (56 deaths) in the control group (P=0.06). The number of deaths from cardiovascular events was lower in the intervention group (8 deaths, 0.6%) than in the control group (23 deaths, 1.7%), (P=0.006) (Table S5).


Figure 2.Subgroup Analyses for Change in Systolic Blood Pressure at 24 Months, According to Participant Characteristics at Baseline.

The results with respect to the intervention effect were consistent in sensitivity analyses that used models for each time point separately (Table S6). The cluster-level analysis, which takes a summary measure for each cluster (as opposed to the primary analysis, which is at patient level but accounts for clustering), also showed consistent results (Table S7). The results with respect to the intervention effect were also consistent in the prespecified subgroups (Figure 2 and Table S8), post hoc subgroups (Fig. S5), and country-specific analyses (Tables S9 through S11).


The estimated cost of scale-up per eligible patient with hypertension in rural areas in Bangladesh, Pakistan, and Sri Lanka was $10.70, $10.50, and $4.70 (U.S. dollars), respectively (Table S12).


In a cluster-randomized trial involving adults with hypertension in villages in Bangladesh, Pakistan, and Sri Lanka, blood-pressure control was improved by a multicomponent intervention, which included community health workers, was tailored to the rural setting, and was delivered through the existing public health care infrastructure. The intervention also increased adherence to antihypertensive medication and improved some aspects of participant-reported health at an annual cost of less than $11 per patient. The major strengths of our trial are a cluster design; rural settings in three countries, with stratification according to the distance from the clinic; the inclusion of all adults with hypertension (uncontrolled and controlled); excellent recruitment and retention rates; and a prespecified and prepublished statistical analysis plan.16

During this 24-month trial, the benefit of the intervention with respect to blood-pressure lowering increased with a longer duration of follow-up, which suggests potential longevity of the intervention effect. Although our trial was not designed to dissect the relative contributions of each component of the intervention on the effect, our previous work indicated synergies among the components10,11; the current trial suggests that appropriate use of medications may have played a substantial role. For example, participants with elevated blood pressure were referred to clinics in which trained physicians prescribed a greater number and a higher dose of antihypertensive medications than in the control group, coordinators facilitated tracking, and community health workers monitored blood pressure and reinforced messages about adherence during repeated home visits. The annual retraining of community health workers and physicians may have enhanced their competencies over time.

Many systematic reviews largely from high-income countries have shown the benefit of multicomponent strategies on hypertension control.26 Our trial is different from previous studies that have either focused primarily on urban populations12,13,27 or used technology to deliver interventions in rural environments with conflicting results on blood-pressure reduction.27-30

Community health workers are an integral part of the primary care infrastructure for the successful delivery of maternal and child health care in South Asia,31 as well as in China, Mexico, and Africa.32-34 Our findings show that community health workers who are employed in the public sector can have an important role in managing hypertension.

Our trial has limitations. First, the intervention effect could have been underestimated because participants in the usual-care group may have modified their behavior in response to blood-pressure measurements performed by researchers to assess outcomes. Second, the trial was underpowered to detect changes in many secondary outcomes. Third, the short duration meant that there was insufficient power to assess cardiovascular events. However, a reduction of 2 mm Hg in systolic blood pressure has been associated with a reduction of 7 to 10% in the risk of coronary heart disease, stroke, and related death.35-37

Our findings have public health implications. Cardiovascular mortality continues to rise in low- and middle-income countries, especially in rural areas with a high burden of poverty and fragmented health systems.9 There is ample evidence of the benefit of blood-pressure reduction on cardiovascular mortality; however, affordable strategies for blood-pressure control are lacking. Our low-cost intervention (<$11 per patient annually), if scaled up, might translate into substantial reductions in premature deaths and disability, as well as social and economic returns.38,39 Discussions with provincial health departments and national advisory committees are ongoing to facilitate the scale-up of the intervention in the three countries, with the same fidelity as implemented in the trial.

We found that a multicomponent intervention for hypertension care, which centered on proactive home visits by trained government community health workers who were linked with existing public health care infrastructure, led to a clinically meaningful reduction in blood pressure in rural communities in Bangladesh, Pakistan, and Sri Lanka.

Supported by a grant (MR/N006178/1) from the Joint Global Health Trials scheme, which includes the Medical Research Council, the U.K. Department for International Development, the National Institute for Health Research, and the Wellcome Trust.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

Drs. Gandhi, de Silva, Jehan, and Naheed contributed equally to this article.

data sharing statement provided by the authors is available with the full text of this article at NEJM.org.

We thank all the investigators, coordinators, and staff of the trial at the respective institutions, including at the International Center for Diarrheal Disease Research, Bangladesh (Dhaka); Aga Khan University (Karachi, Pakistan); the Faculty of Medicine, University of Kelaniya (Ragama, Sri Lanka); the London School of Hygiene and Tropical Medicine (London); and Duke–NUS Medical School (Singapore, Singapore). We also thank all the members of the trial steering committee and the data and safety monitoring committee (listed in the Supplementary Appendix) and all the trial participants, without whose cooperation the trial would not have been possible.

Author Affiliations

From the Program in Health Services and Systems Research (T.H.J., E.A.F., L.F.) and the Center for Quantitative Medicine (M.G.), Duke–NUS Medical School, the Department of Renal Medicine, Singapore General Hospital (T.H.J.), and the Department of Biostatistics, Singapore Clinical Research Institute (M.G., P.N.A.) — all in Singapore; the Duke Global Health Institute (T.H.J., E.A.F., E.L.T.) and the Department of Biostatistics and Bioinformatics, Duke University (E.L.T.) — both in Durham, NC; the Center for Child Health Research, Tampere University, Tampere, Finland (M.G.); the Clinical Trials Unit, Department of Pharmacology (H.A.S.), and the Department of Public Health (A.K.), Faculty of Medicine, University of Kelaniya, Ragama, Sri Lanka; the Department of Community Health Sciences (I.J.) and the Section of Cardiology, Department of Medicine (A.H.K.), Aga Khan University, Karachi, Pakistan; the International Center for Diarrheal Disease Research, Bangladesh, Dhaka, Bangladesh (A.N., J.D.C.); the UCLA Fielding School of Public Health, Department of Community Health Sciences, Los Angeles (D.M.); and the London School of Hygiene and Tropical Medicine, London (S.E.).

Address reprint requests to Dr. Jafar at Duke–NUS Medical School, 8 College Rd., Singapore 169857, Singapore, or at tazeen.jafar@duke-nus.edu.sg.

A list of the members of the COBRA-BPS Study Group is provided in the Supplementary Appendix, available at NEJM.org.

Supplementary Material

Supplementary AppendixPDF1628KB
Disclosure FormsPDF242KB
Data Sharing StatementPDF69KB

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    Citing Article (1)


    1. Table 1.Baseline Characteristics of the Participants.*
    2. Figure 1.Mean Change in Systolic Blood Pressure and Diastolic Blood Pressure over Time.Mean changes from baseline were estimated with a generalized linear mixed-effects model for repeated measures for change in systolic blood pressure (Panel A) or diastolic blood pressure (Panel B), with fixed effects for baseline systolic or diastolic pressure, country, distance of the cluster from the clinic, age, sex, time, and interaction of time with trial group and with random effects for clusters. The bars indicate 95% confidence intervals.
    3. Table 2.Intervention Effect on Blood-Pressure Outcomes and Use of Antihypertensive Medications.*
    4. Figure 2.Subgroup Analyses for Change in Systolic Blood Pressure at 24 Months, According to Participant Characteristics at Baseline.Mean changes and differences (intervention − control) were estimated with a generalized linear mixed-effects model for repeated measurements for change in systolic blood pressure, with fixed effects for baseline systolic pressure, country, distance of the cluster from the clinic, age, sex, time, and interaction among time, trial group, and subgroup and with random effects for clusters. Socioeconomic status was defined as low to middle and high on the basis of an International Wealth Index range of the 67th percentile or lower and higher than the 67th percentile, respectively, for each country sample separately. Participants with a systolic blood pressure of 160 mm Hg or more or a diastolic blood pressure of 100 mm Hg or more were considered to have very poorly controlled blood pressure.

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    February 20, 2020
    N Engl J Med 2020; 382:717-726
    DOI: 10.1056/NEJMoa1911965

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