Publisher Health

Accurate linking of an individual’s medical records from disparate sources within and between health systems, known as patient matching, plays a critical role in patient safety and quality of care, but has proven difficult to accomplish in the United States, the last developed country without a unique patient identifier. In the U.S., linking patient data is dependent on algorithms designed by researchers, vendors and others. Research scientists led by Regenstrief Institute Vice President for Data and Analytics Shaun Grannis, M.D., M.S., have developed an eight-point framework for evaluating the validity and performance of algorithms to match medical records to the correct patient.
“The value of data standardization is well recognized. There are national healthcare provider IDs. There are facility IDs and object identifiers. There are billing codes. There are standard vocabularies for healthcare lab test results and medical observations — such as LOINC® here at Regenstrief. Patient identity is the last gaping hole in our health infrastructure,” said Dr. Grannis. “We are providing a framework to evaluate patient matching algorithms for accuracy.
“We recognize that the need for patient matching is not going away and that we need standardized methods to uniquely identify patients,” said Dr. Grannis. “Current patient matching algorithms come in many different flavors, shapes and sizes. To be able to compare how one performs against the other, or even to understand how they might interact together, we have to have a standard way of assessment. We have produced a novel, robust framework for consistent and reproducible evaluation. Simply put, the framework we’ve developed at Regenstrief provides a ‘measuring stick’ for the effectiveness of patient matching tools.”
Individuals increasingly receive care from multiple sources. While patient matching is complex, it is crucial to health information exchange. Is the William Jones seen at one healthcare system the same person as the William, Will or Willy Jones or perhaps Bill or Billy Jones receiving care at other facilities? Does Elizabeth Smith’s name appear at different medical offices or perhaps at a physical therapy or a dialysis facility as Liz or Beth? To which Juan J. Gomez do various lab test results belong? Typos, missing information and other data errors as well as typical variations add to the complexity.
The framework’s eight-point approach to the creation of gold standard matching data sets necessary for record linkage encompasses technical areas including data preprocessing, blocking, record adjudication, linkage evaluation and reviewer characteristics. The authors note that the framework “can help record linkage method developers provide necessary transparency when creating and validating gold standard reference matching data sets. In turn, this transparency will support both the internal and external validity of recording linkage studies and improve the robustness of new record linkage strategies.”
Measures and standards are ubiquitous. “When you go to a gas station pump, the measure of how much gas goes through is standardized so that we know exactly how much is flowing. Similarly, we need to have a common way of measuring and understanding how algorithms for patient matching work,” said Dr. Grannis. “Our eight-pronged approach helps to cover the waterfront of what needs to be evaluated. Laying out the framework and specifying the tasks and activities that need to be completed goes a long way toward standardizing patient matching.”
In addition to playing a critical role in patient safety and quality of care, improved patient matching accuracy supports more cost-effective healthcare delivery in a variety of ways including reduction in the number of duplicate medical tests.

Technology that enables an unprecedented, high-resolution look for all structural variants in our genes that are known to cause cancer can outperform standard tests used today for common blood cancers like leukemia, researchers report.
It’s called optical genome mapping, or OGM, a longtime research tool now making its way into health care.
Now the first study to standardize precisely how to use OGM for patients with a wide range of blood cancers indicates it can duplicate what existing tests find, provide better insight on the variants those tests identify and find additional variants, information that should improve patient outcomes.
“This is the first study to try to standardize the way we need to investigate these structural changes in hematologic malignancies using OGM for patients,” says Ravindra Kolhe, MD, PhD, molecular pathologist and interim chair of the Department of Pathology at the Medical College of Georgia at Augusta University.
“The bottom line is that by using technology like this, we will be able to make a better, more specific diagnosis, better classify the cancer, give a better prognosis based on that classification and enable better therapy choices,” says Kolhe, corresponding author of the study published in The Journal of Molecular Diagnostics.
The findings demonstrate OGM’s potential as a frontline test in diagnosing blood cancers, or hematologic malignancies, says Kolhe, associate director of genomics at the Georgia Cancer Center. Often, more than one of the three current tests are done on a single patient, and OGM may eliminate the need for multiple tests, the investigators say.

OGM enables a direct look at DNA that, as the technology’s name implies, provides a perspective that is 20,000 times closer than conventional, commonly used karyotyping. Karyotyping, which looks for chromosomal abnormalities, is one of the techniques used to analyze blood cancers. Others include chromosomal microarray, which looks for genetic deletions or duplications at a higher resolution than karyotyping but nowhere near that of OGM; and fluorescence in situ hybridization, or FISH, which also looks directly at DNA but on a much smaller, and less high-resolution scale, than OGM.
A key problem has been the comparatively low resolution of the technologies, which Kolhe likens to looking at the sky with the naked eye.
“This what is known as whole genome mapping,” says Kolhe. “This looks genome-wide for structural variants.”
DNA is a fundamental unit of our genetic material that makes us, genes are segments of our DNA and DNA is carried in chromosomes which are found in our cells. It’s a patient’s symptoms and a typically subsequent look at cells in their blood that first indicate cancer is present. But it’s these structural variants in the genes in those cells that are a major cause of cancer and can tell you the specific cancer type and stage, Kolhe says.
Structural variations, which can alter the gene’s normal function into a cancer-promoting mechanism, include things like duplication or deletion of a gene and two genes swapping places in a process called translocation which, for example, might make the gene more active. Genes can even “fall out,” which can be problematic if, for example, one of those genes is a natural tumor suppressor like the p53 gene.

Kolhe notes his frustration over the years at looking at the findings of low-resolution techniques like karyotyping that have prevented identification of specific structural variants.
As an example, with today’s standard technologies, pathologists have a category called “karyotypically normal leukemia,” a true oxymoron, he says, because there are clearly one or more abnormalities causing the cancer but the pathologists looking for them cannot see them and/or cannot see them well.
Kolhe and colleagues at MCG, Emory University’s Department of Pathology and San Diego-based Bionano Genomics Inc., which developed an OGM system called Saphyr, decided to look at how to standardize OGM’s use in analyzing a wide range of blood cancers and see how its findings stack up to current methods.
They looked at 59 samples of blood, isolated cells and lymph nodes and bone marrow, some of them multiple times for the purpose of validation. The patients had a variety of common blood cancers, such as chronic lymphocytic leukemia and lymphoma, and there were 10 control samples from individuals without cancer. One or more of the standard tests had been performed on each patient’s samples including 10 leukemia samples that were classified normal by karyotyping, 45 classified as simple cases, meaning there were less than four structural variants found, and 14 as complex with four or more variants.
As examples of what OGM found, it confirmed all but two of the 164 variants found by traditional methods. But in the 10 leukemia samples that were classified as normal by karyotyping, structural variations were detected in 40% by OGM. Seven of the samples that were classified as simple by both FISH and karyotyping were found to have four or more aberrations, which would classify the cancers as complex. Five of the seven samples classified as simple based on just FISH testing, showed four or more aberrations with OGM, and OGM was able to further delineate some individual variants in both these groups. For example, in chronic lymphocytic leukemia, OGM was able to distinguish minute changes in common deletions associated with the cancer that moved the prognosis from good to poor. It was also able to detect 106 novel gene fusions. Gene fusions are when a new gene results from joining parts of two different genes, which may lead to developing some cancer types, according to the National Cancer Institute. Current techniques like FISH are not proficient at identifying new gene fusions.
Kolhe notes use of OGM should result in about 20% of patients at least getting a change in the classification of their malignancy, say from low- to mild-risk, which makes a difference in treatment choices. These more refined diagnoses are needed to make optimal use of the unprecedented numbers of targeted treatment options today, he notes.
“Our first goal was to confirm those abnormalities with this technique,” Kolhe says. “On top of that, we showed optical genome mapping adds a substantial layer of clinically relevant information about that patient.”
The standardization of the technique was necessary to establish precisely how to use OGM on patients to obtain consistently, accurate results.
Other investigators also have been exploring OGM’s potential in specific cancers like acute lymphoblastic leukemias and larger groups of cancer types as well.
There already is some movement in places like Europe and Canada to move away from longtime approaches like FISH and move toward OGM. Kolhe hopes the newly published information about how to use OGM for patients will help do the same in this country.
Later this month, the Georgia Cancer Center will be the first to use OGM for patient care in the United States, Kolhe says. While many centers do not have the OGM technology, providers can send their patients’ cells to MCG’s Georgia Esoteric and Molecular Lab for testing effectively immediately.
There are structural variants you can be born with, which are responsible for genetic disorders, or you can acquire them through environmental exposures like cigarette smoke or obesity.

When the idea struck him, nearly 50 years ago, Dr. Étienne-Émile Baulieu believed it could be revolutionary. Creating a pill that could abort a pregnancy would transform reproductive health care, he thought, allowing women to avoid surgery, act earlier and carry out their decisions in private.“When science meets women’s cause, it is irresistible,” Dr. Baulieu, 96, a French endocrinologist and biochemist often called the father of the abortion pill, said on a recent Sunday afternoon in his apartment in a century-old building a short walk from the Eiffel Tower.He had also hoped, as he wrote in a 1990 book, that by the 21st century, “paradoxically, the ‘abortion pill’ might even help eliminate abortion as an issue.”That prospect seems as distant as ever, especially in the United States. Not only has abortion remained fiercely contentious since the pill Dr. Baulieu spearheaded, mifepristone, was approved in America in 2000, but last year’s Supreme Court decision ending the federal right to abortion has divided the country over the issue as never before.Yet over time, some of Dr. Baulieu’s other expectations have materialized. Today, medication abortion, in which mifepristone and a second drug are taken early in pregnancy, is used in over half of pregnancy terminations in the United States. That proportion is expected to increase, even in states that have banned abortion, where growing use has put the pills at the center of legal and political battles.For Dr. Baulieu, who continues work in his lab on the southern rim of Paris, his office overlooking a former asylum where the Marquis de Sade was held, the volatile developments are just the latest turns in an eventful life. He transported guns as a teenager in the French Resistance during World War II, changing his name and taking refuge high in the Alps. He joined the Communist Party and then quit it in 1956 after the Soviet invasion of Hungary. And he socialized with the artists Andy Warhol and Jasper Johns in the 1960s, beginning a pattern of friendships with painters, sculptors, musicians and actors that he said had helped inspire his scientific work.Dr. Baulieu continues to work at his lab at the Kremlin-Bicêtre Hospital on the southern edge of Paris. Julie Glassberg for The New York TimesMifepristone, typically followed by misoprostol, is now used in more than half of U.S. pregnancy terminations.Gabriela Bhaskar for The New York TimesThat work has earned Dr. Baulieu many scientific honors, including the Lasker Award, often considered the most prestigious American prize in medicine. Recently, France’s president, Emmanuel Macron, awarded him the Grand Cross of the Legion of Honor, the highest distinction. Admirers have floated his name for a Nobel Prize.For his leading role in developing mifepristone, he has been hailed as a visionary by abortion rights supporters and vilified as an incarnation of Hitler by abortion opponents, a charge that he said he found especially jarring because he is Jewish.Although he and the pill have become lightning rods, Dr. Baulieu speaks of the abortion debate without vitriol, cognizant of the complexity of the issue.“When he believes something, he’s quite relaxed,” said Simone Harari Baulieu, who has been his romantic partner for over 25 years and became his second wife in 2016.With a medical degree and a Ph.D. in biochemistry, Dr. Baulieu has always considered himself “a doctor who practices science,” looking for ways to translate research into useful applications.Scientifically and medically, “women are not enough understood,” he said, adding: “I like women. Why not?”An independent streakDr. Baulieu’s office is jumbled with memorabilia, papers, books, art and a chalkboard with sketches of how the brain processes memories.Julie Glassberg for The New York TimesEclectic artifacts fill the home Dr. Baulieu shares with his wife, who runs a film and television production company.In a portrait by the photographer Richard Avedon, Dr. Baulieu wears a black turtleneck and holds a small white pill. A surrealist painting of him and Ms. Harari Baulieu by the contemporary French artist Gérard Garouste hangs above an ornate fireplace.Shelves overflow with books: Maimonides’s “The Guide for the Perplexed”; a history of “Old Shanghai”; a collection of excerpts from Proust. More books are piled on the living room’s parquet wood floor, near windows overlooking a narrow balcony edged by an ornamental iron railing.On the dining room table are two recent gifts from Vice President Kamala Harris. Her late mother, Shyamala Gopalan Harris, a breast cancer researcher, spent about a year working in Dr. Baulieu’s lab in the 1980s, collaborating with him on research about estrogen and a mammary gland protein. (She did not work on the abortion drug.)On an official trip to France in 2021, the vice president met privately with Dr. Baulieu and his wife. She gave them a glass bowl and the French translation of her book, inscribed: “Thank you for your friendship and all you do and mean to our family. Love, Kamala.” Last month, in remarks at a luncheon for Mr. Macron in Washington, Ms. Harris mentioned her mother’s work with “the legendary French Professor Baulieu.”Dr. Baulieu’s instinct for innovation may have come from his father, Dr. Léon Blum, a kidney specialist who was one of the first doctors to use insulin for diabetics and who treated an Egyptian king’s diabetes while on his honeymoon with Dr. Baulieu’s mother.In World War I, Dr. Blum, who was from German-occupied Alsace, was drafted by the German Army. But he surreptitiously aided France by asking German officers he treated to mail him postcards about how much urine they were producing; he used the postmarks to gauge German troop movements and gave that intelligence to the French military. Eventually, he fled to France, where he was awarded the Legion of Honor.He died at age 54 when his son, born Étienne Blum, was only 3. Étienne’s mother, Thérèse Lion, a lawyer and conservatory-trained pianist, moved her three children to Paris.“She believed that my father died because of contamination from sick people,” Dr. Baulieu said. She told him he could become anything he wanted, except a doctor. “And the only thing I chose was to become a physician,” he said.Photos in Dr. Baulieu’s office show him with his father, left, Léon Blum, a kidney specialist, and his mother, Thérèse Lion, a lawyer and pianist.Julie Glassberg for The New York TimesMax-Fernand Jayle, who studied hormonal processes in women, was a mentor to Dr. Baulieu and gave him opportunities early in his career.Julie Glassberg for The New York TimesHis independent streak was honed long before that, though. During World War II, his family fled German-occupied Paris for Grenoble, and at 15, he and classmates distributed anti-Nazi leaflets and “threw stones at people who were working for Germans,” he said.Two years later, he was in a cafe when he noticed men lurking outside and realized, “I was detected by the Germans.” He slipped out the back and left town without saying goodbye to his mother.When he joined French Resistance members in the alpine towns of Chamonix and Annecy, they suggested he change his name, offering several options, including “Beaulieu,” which means “beautiful place.” He liked that, but felt it would be pretentious to adopt “beautiful” as a name, so he changed the spelling to “Baulieu” and chose “Émile” as a first name.His group’s activities included ferrying arms and kidnapping and executing an imprisoned Vichy official.“I was too young to shoot,” Dr. Baulieu said, “so they gave me a camera,” which he used to photograph the execution.“I hated the violence, but they were really enemies and traitors,” he said.Like fellow French Resistance members, he joined the Communist Party but declined to become a party official after the war. Instead, he went to medical school.He joined the lab of a scientist, Max-Fernand Jayle, who had been blinded during an experiment. Dr. Baulieu said other students thought working for Dr. Jayle would be a career dead end, but he considered Dr. Jayle inspiring and original.An encouraging mentor, Dr. Jayle, who studied hormonal processes in women, gave Dr. Baulieu advanced opportunities that allowed him to become a tenured professor at 31.In an important early discovery that had eluded many scientists, Dr. Baulieu determined how to detect a hormone, dehydroepiandrosterone, or DHEA, which helps produce estrogen and testosterone and can signal diseases like adrenal cancer.“I did it with a simple idea which, in classical terms, made little sense,” he wrote. Instead of looking in oily extracts from the adrenal glands, he found a water-soluble form in urine, “like probing a vinaigrette: looking in the vinegar instead of the oil.”Vice President Kamala Harris gave Dr. Baulieu a bowl emblazoned with the vice presidential seal. Her mother, Shyamala Gopalan Harris, a breast cancer researcher, spent about a year working in Dr. Baulieu’s lab in the 1980s.Pam Belluck/The New York TimesA sculpture, called “Nana,” with parts by Niki de Saint Phalle, left, and Jean Tinguely, right, in Dr. Baulieu’s office.Julie Glassberg for The New York TimesThat earned him an invitation to spend a year at Columbia University with Dr. Seymour Lieberman, a steroid expert. But Dr. Baulieu’s previous Communist ties led the Eisenhower administration to repeatedly reject his visa application, despite pleas from fellow scientists, and he obtained a visa only after John F. Kennedy became president.On the ship to New York in 1961, Dr. Baulieu met Barbara Rose, a prominent art historian. She introduced him to up-and-coming artists, including Frank Stella (whom she later married), Mr. Johns, Mr. Warhol and Robert Rauschenberg.“I realized from my artist friends the similarity of creation in science and art,” Dr. Baulieu wrote.His admiration for creative people endured, leading to close friendships and occasional romances. During his long marriage to his first wife, with whom he had three children, he had several romantic relationships, he said, adding, “I knew a number of beautiful, interesting, intelligent and free women.”One relationship was with Niki de Saint Phalle, whose riotously colorful paintings and sculpture are displayed in his home and laboratory office. In the late 1970s, at the French Riviera home of the conductor Herbert von Karajan, Dr. Baulieu met the actress Sophia Loren, and he said they had a romantic relationship while both were married to other people. At one point, they were photographed in a car. “I was in love, yes,” Dr. Baulieu said. The relationship ended, he said, because she was devoted to raising her children and wanted to preserve her marriage. A representative for Ms. Loren declined to respond to questions. In 1991, Ms. Loren told Vanity Fair, “I was never involved with him.”An ‘unpregnancy pill’Dr. Baulieu in 1984, holding an abortion pill.Arnaud Borrel/Gamma-Rapho, via Getty ImagesDr. Baulieu’s path to developing the abortion pill began in 1961 with a speaking invitation from Gregory Pincus, who helped invent the birth control pill. Dr. Pincus, then a co-director of the Worcester Foundation for Experimental Biology in Massachusetts, became another mentor. He suggested that Dr. Baulieu travel to Puerto Rico to observe clinical trials of the contraceptive pill.“When I saw what they were doing in Puerto Rico, it was remarkable for the treatment of women,” Dr. Baulieu said.Back in Paris, Dr. Baulieu, who directed a unit at France’s National Institute of Health and Medical Research, rejected an offer to become head of research at the pharmaceutical company Roussel-Uclaf, but agreed to become a part-time consultant. The arrangement allowed him to use some company laboratories and molecules for research but barred him from earning money from any Roussel-Uclaf products.He began thinking of potential advances in reproductive medicine. During his medical residency, he’d learned that some women seeking to terminate pregnancies would insert sticks to cause miscarriages and would then go to the hospital. He was shocked that some surgeons instructed employees not to give anesthesia. “‘Teach her a lesson she’ll remember,’ I heard one of them say,” he wrote.In 1970, Dr. Baulieu was visiting India with a group of intellectuals when a woman begging on a bridge in Kolkata, then known as Calcutta, approached him while cradling her dead baby and holding the hand of a child who held another one of her children.“It really caused an emotion for me, which has persisted all my life,” he said. “I think always of Calcutta as something which has pushed me to really work hard.”He started brainstorming an idea for an “unpregnancy pill.” It would involve a kind of biological sleight-of-hand.The lab at Kremlin-Bicêtre Hospital.Julie Glassberg for The New York TimesDr. Baulieu described the work of RU-486 as “contragestion” because it counteracted the gestation process. More simply, he wrote, “RU-486’s action is like jamming a radio signal.”Julie Glassberg for The New York TimesThe hormone progesterone is pivotal in pregnancy because it prepares the uterus to receive and hold an embryo. What if progesterone could be prevented from delivering its cellular messages?“I wanted to create an anti-hormone,” Dr. Baulieu said.In guinea pigs, his team identified receptor molecules that progesterone connected with to convey messages. Dr. Baulieu suggested trying to make a faux progesterone, an impostor to latch onto progesterone receptors so the real hormone could not.He asked Roussel-Uclaf’s chemists to try grafting a cluster of atoms onto a molecule with progesterone’s structure so it would be similar enough to bind to the progesterone receptor.The leader of the German company that was Roussel-Uclaf’s majority stakeholder, Hoechst AG, was a staunchly anti-abortion Catholic, Wolfgang Hilger. To avoid controversy in meetings with company officials, Dr. Baulieu said, he emphasized a non-abortion-related property of an antiprogesterone compound: Because it would also block receptors for the stress hormone cortisol, it could theoretically treat burns, wounds, glaucoma and other conditions.In 1980, Roussel-Uclaf’s chief chemist, Georges Teutsch, synthesized a compound that worked as Dr. Baulieu had envisioned.“Although neither Teutsch nor most of the others in the company initially realized it, it was also what I wanted: an antiprogesterone,” Dr. Baulieu wrote. Registered as Roussel-Uclaf 38486, the company’s 38,486th molecule, it was nicknamed RU-486.“It’s like a key in a lock,” Yvette Akwa, a researcher in Dr. Baulieu’s lab, explained recently. “You make a similar key that fits the lock. And then when progesterone would go to open the door, it can’t because it’s already blocked.”Dr. Baulieu called the concept “contragestion” because it counteracted the gestation process. More simply, he wrote, “RU-486’s action is like jamming a radio signal.”After other scientists tested RU-486 on rats and monkeys, Dr. Baulieu urged Roussel-Uclaf to allow human trials and asked an obstetrician-gynecologist friend in Switzerland, Dr. Walter Herrmann, to conduct them. In 1982, a trial found that RU-486 aborted early pregnancies in nine of 11 patients. Later trials showed that by following RU-486 with a prostaglandin, a medication that causes contractions, the method was about 95 percent effective. Today, RU-486 — mifepristone — is followed 24 to 48 hours later by a synthetic prostaglandin called misoprostol.A demonstration against RU-486 outside the headquarters of Roussel-Uclaf in Paris in 1991.Jean-Michel Turpin/Gamma-Rapho, via Getty Images“Up to then, abortion had not been proposed in a way which, at the same time, is efficient, safe and not too difficult for women,” Dr. Baulieu said.Abortion opponents pilloried the company, swarming a shareholders’ meeting. Drawing analogies to Hoechst’s predecessor company, I.G. Farben, which made the cyanide gas used in Nazi death camps, some shouted, “You are turning the uterus into a crematory oven,” Dr. Baulieu wrote.In Washington, an anti-abortion campaign flooded the French Embassy with letters threatening to boycott French products if France approved the pill. The company almost withdrew its application. In September 1988, the French authorities approved RU-486.Several days later, debating Dr. Baulieu on French television, Dr. Jérôme Lejeune, an anti-abortion pediatrician who discovered the genetic basis of Down syndrome, called RU-486 “the first anti-human pesticide” and said it would “kill more human beings than Hitler, Mao Zedong and Stalin combined.”“You can’t say it’s like Hitler,” Dr. Baulieu exclaimed. “Don’t say things that would make me laugh if this weren’t a serious debate.”The clamor from opponents was so intense that a month after the approval, Roussel-Uclaf said it would stop marketing RU-486. Dr. Baulieu wrote that the company’s chairman, Dr. Edouard Sakiz, told him that he feared a violent incident, like one that month when an ultraconservative group set fire to a Paris movie theater showing “The Last Temptation of Christ.”But Dr. Sakiz told Dr. Baulieu he was free to speak out. Dr. Baulieu flew to Brazil for the World Congress of Gynecology and Obstetrics, where doctors and researchers vehemently decried Roussel-Uclaf’s withdrawal of RU-486.Soon afterward, Claude Évin, the health minister of France, which owned part of Roussel-Uclaf, called RU-486 “the moral property of women” and pressured the company to resume selling it. “I could not permit the abortion debate to deprive women of a product that represents medical progress,” he said.A poster advertised a conference Dr. Baulieu spoke at in China in the 1990s.Julie Glassberg for The New York TimesDr. Baulieu in his uniform from the French Academy of Sciences.via Étienne-Émile BaulieuAfter RU-486’s approval, Dr. Elisabeth Aubény, an obstetrician-gynecologist, said her hospital gave it to appreciative patients, but also encountered protesters who chained themselves to operating tables.Beginning in the 1980s, Dr. Baulieu received hate mail, some of it antisemitic. A poster in Canada featured Dr. Baulieu’s photo and the words “Wanted for Genocide.” One in San Francisco equated him with the Nazi death camp doctor Josef Mengele, calling them “blood brothers.” In New Orleans, a small bomb exploded at a conference at the time Dr. Baulieu would have been speaking if not for travel delays, he said.He also received grateful letters from America and pleas for the pill to be available there. Some at Roussel-Uclaf felt he hadn’t shared enough credit for RU-486. Not long after Dr. Baulieu won the Lasker Award, Dr. Teutsch, the chemist, was quoted as saying, “Étienne Baulieu is the father of the pill, but he is not the father of the compound.”For years, afraid that opposition in America would lead to boycotts of its other products, the company declined to seek approval of RU-486. In 1993, an abortion rights organization started a clandestine lab to make the pill in a suburban New York warehouse. In 1994, with the Clinton administration championing the pill, Roussel-Uclaf donated American rights to the Population Council, a nonprofit organization.The Food and Drug Administration gave RU-486 conditional approval in 1996, but large pharmaceutical companies wouldn’t manufacturer it, and full approval didn’t occur until 2000, after a small company, Danco Laboratories, agreed to make it.Today, as some states ban nearly all abortions and propose actions to target medication abortion, other states and the Biden administration have taken steps to expand access to abortion pills. Patients can have consultations with abortion providers via telemedicine and receive the prescribed pills by mail. A new F.D.A. rule will allow retail pharmacies like CVS to fill prescriptions for the pills. And in states with abortion bans, many patients order pills from an overseas telemedicine abortion organization.Still at workThe building containing Dr. Baulieu’s lab is named for one of his mentors: Gregory Pincus, an American scientist who helped invent the birth control pill.Julie Glassberg for The New York TimesThese days, scientific experimentation continues apace at Dr. Baulieu’s lab in the Grégory Pincus building, a boxy, teal-colored structure on a hospital campus that was previously the site of an 18th century prison.Dr. Baulieu has made discoveries about various steroid hormones, including the finding that some are synthesized in the brain; he called them “neurosteroids.” Today, his team studies Alzheimer’s and has started clinical trials on a new method to treat severe depression, based on Dr. Baulieu’s ideas about a receptor for a particular neurosteroid.“He discovered both the receptor and the function,” said Isabelle Villey, a biochemist who leads a small company headquartered at Dr. Baulieu’s lab.Dr. Baulieu’s office is jumbled with memorabilia, papers, books and art. Near a chalkboard with sketches of how the brain processes memories, there are avant-garde sculptures by his artist friends — including a mechanized representation of the sword he received upon being inducted into the French Academy of Sciences, where he later served as president. Recently, warmed by a scarf and a puffy down vest under a blazer, he gave an impromptu seminar, thumbing through one of his RU-486 articles.He remains energetic, barely slowed by his use of a cane and displaying only occasional hiccups in memory.Over dinner at a Montparnasse seafood restaurant, Dr. Baulieu said he was dismayed by anti-abortion politics and what he called the “scandalous” Supreme Court ruling in America. But, he said, “it’s good that my pill is accepted by a large number of women.”His outlook has been shaped by living nearly a century, marked by war, social upheaval and scientific innovation.“I’m optimistic,” Dr. Baulieu said, “because science helps you to be optimistic.”In his office, Dr. Baulieu gave an impromptu seminar about one of his scientific papers on RU-486.Julie Glassberg for The New York Times

The stories the mothers tell when they gather at the Awendo Health Centre in western Kenya are a catalog of small failures, missed opportunities and devastating consequences. What unites the two dozen or so women who meet periodically, on wooden benches in a bare clinic room or under a tree in the courtyard, is their children: All have H.I.V.It has been two decades since efforts to prevent the transmission of H.I.V., the virus that causes AIDS, from mother to child during pregnancy and birth began in earnest in sub-Saharan Africa. Yet some 130,000 babies are still becoming infected each year because of logistical problems, such as drug shortages, and more pernicious ones, such as the stigma that makes women afraid to seek tests or treatment.Then, many of the children who contract the virus are failed a second time: While the effort to put adults on H.I.V. treatment has been a major success across the region, many children’s infections are undetected and untreated.Seventy-six percent of adults living with H.I.V. are on treatment in sub-Saharan Africa, according to U.N.AIDS, a United Nations program. But just half of children are.An estimated 99,000 children in sub-Saharan Africa died of AIDS-related causes in 2021, the last year for which there is data. Another 2.4 million children and adolescents in the region are living with the virus, but just over half have been diagnosed. AIDS is the top cause of mortality for adolescents in 12 countries in East and Southern Africa.“The focus for a decade in the global AIDS response has been controlling the epidemic, and it’s amazing that treatment has reached so many adults,” said Anurita Bains, who heads global H.I.V./AIDS programs for UNICEF. “But children aren’t going to spread H.I.V., so they dropped down the priority list. They’ve been almost forgotten.”She added: “Children with H.I.V. are harder to find than adults, we have fewer tools to test and treat them, and they rely on their caregivers to access health care.”Migori, a town in western Kenya, has one of the highest rates of H.I.V. prevalence in the country. Many clinics here haven’t had H.I.V. tests to give pregnant women for several years.Preventing a woman from passing H.I.V. to a child at birth is, in theory, relatively straightforward. The national policy in every sub-Saharan African country with a high prevalence of H.I.V. stipulates that all pregnant women are to be screened for the virus and that those who test positive should start treatment right away.To catch any missed cases, women are supposed to be tested again when they are in labor. If they are positive and not on treatment, they are to be given drugs to block transmission. Their babies should be given another drug for the first six weeks of life. In more than 90 percent of cases, this protocol is enough to prevent a child from becoming infected. A mother on H.I.V. treatment has a low risk of infecting a child while breastfeeding.The Fight Against H.I.V.An estimated 40 million people are living with H.I.V. worldwide. About 10 million of them do not have access to treatment.A New Shot: An injection every two months rather than a daily pill could shield many more women from H.I.V., but the shot is unavailable in places that need it most.Pandemic Setbacks: Before Covid-19, the world had been making strides against global illnesses like H.I.V. The pandemic has changed that for the worse.A Visionary: Ravindra Gupta led the efforts that resulted in the second case of a patient being cured of H.I.V. Then he was drawn into Covid research.A Promising Treatment: In February, researchers announced that a woman became the third person ever to be cured of H.I.V. thanks to a new transplant method that could help more people from racially diverse backgrounds.But progress has flatlined in several countries in the last five years, and the Covid pandemic set it back further, with disruptions to the supply of tests and drugs, clinic shutdowns, staff shortages and a shifting away of attention to the fight against AIDS.“It’s very painful when you are with a pregnant woman who is almost delivering and there is no medication and you wonder, Will the child be positive or not?” said Caroline Opole, who is a volunteer “mentor mother,” counseling women who test positive for H.I.V. at prenatal testing as she did.A pharmacist packed a bottle of antiviral pills at the pharmacy at the Ogwedhi Health Centre in Migori.The stories from the mothers at the Awendo clinic underscore the routine failings seen across the health system here: The clinic was out of tests. The clinic was out of drugs. The lone overworked nurse was too busy to deliver a vital dose of medication when a woman was in labor.“Prevention of mother-to-child transmission, whereas there has been a lot of effort to scale it up, has not performed as well as we should have done,” said Dr. Andrew Mulwa, director of medical services for the national health ministry in Nairobi.Laurie Gulaid, UNICEF’s Nairobi-based regional adviser on H.I.V./AIDS, said the problem here in Kenya and beyond was the gulf between written policy and what the government actually funds, makes a priority and puts into practice in primary health centers such as Awendo.“The intentions are good, but the infrastructure, the resources, the training, the staff — those aren’t there yet, not the way they need to be,” she said.In Migori, a county in the region that has one of the highest rates of H.I.V. prevalence in Kenya, many public clinics haven’t had H.I.V. tests to give pregnant women for several years. Depending on whom you ask, this is because of supply chain disruptions, disputes with donors or poor planning by officials. If women know they have H.I.V., then sometimes their babies are on antiretroviral medication. But sometimes those pediatric drugs are out of stock, too.Ms. Bains of UNICEF said countries needed to redouble their commitment to children. “We need to find the kids we’ve missed, test them, get them on to treatment,” she said. “We need resources to do this, but it also requires robust health care systems and capacity — nurses in clinics and community workers supporting mothers.”Joyce Achieng, left, with her children and others at her home in a village outside Migori. She has struggled to get treatment for two who have H.I.V.Closing the treatment gap for children will also take political will, she added. “When international funding is being allocated to a country, we need to always ask, How will the money be used to reach and support children living with H.I.V.?”But even when the drugs are available, it is not always as simple as taking them, as Joyce Achieng knows. Ms. Achieng was not screened for H.I.V. when pregnant with her first two children, now 12 and 10. She learned she was infected after being tested while pregnant with her third, a girl who is now 7.But a woman in this region is accused of infidelity if she tests positive, Ms. Achieng said, and she feared she might be assaulted or driven from her home if she told her husband.At the time, her husband was working in another part of the country, so she could begin H.I.V. treatment and give the drugs to the baby after her birth while keeping the news to herself. Her daughter tested negative for H.I.V. at age 2. When the clinic encouraged Ms. Achieng to bring her other children in for testing, she did and learned they were negative, too.A year later, she became pregnant again, but this time her husband was home. She couldn’t always hide the drugs she needed for herself or the new baby, another girl. It was hard to come up with excuses to walk the eight kilometers to the clinic to pick up medications or a reason that she needed 100 shillings (about a dollar) for a motorbike taxi. So neither she nor the baby took the drugs consistently, and the infant tested positive for H.I.V. at 6 weeks old.“I cried for the longest time,” Ms. Achieng said. The nurse who gave her the news urged her to start treatment for herself and her daughter again, but she was overwhelmed with guilt and despair.“I said, What is the use, if I have made my own child sick?”Nancy Adhiambo, left, and her children outside her home in Ogwedhi in Migori County, Kenya.Eventually, some tenacious medical staff and volunteers helped her tell her husband she had H.I.V. and to resume treatment. Today, Ms. Achieng is fit and cheerful, and her daughter runs into the house after school to show her a page where she has labeled and colored fruits and shapes. She giggles softly when her older brother takes her for rides in a wheelbarrow.Her daughter takes a pediatric formulation of a drug called Dolutegravir. A highly effective antiretroviral medicine, it recently became available as a strawberry-flavored syrup, which spares parents from battling to get small children to swallow pills each day.“The new drugs do wonders,” said Tom Kondiek, the pediatric clinical officer at the main public hospital in Migori. “Children who are on their deathbed, you start them on medication and then you see them very active and you would not even know they are suffering from H.I.V.”But to start them on medication, health workers must know the children have the virus, and that is where the system breaks down, he said. They may be brought to a clinic over and over but never be tested because staff don’t think of it for a child of 4 or 5, or because there are no tests available.Even when individual women are diagnosed and connected with treatment, health systems too often fail to think of their families, Ms. Gulaid said. In routine care, children are typically seen at 6 weeks old for immunizations and a nutrition screening, but H.I.V. tests are included only for babies known to have been exposed. Other children may not be seen again unless they fall very sick, and it is not standard practice to test all children, the way the clinic did with Ms. Achieng’s.Ms. Adhiambo, picking up her antiretroviral drugs from the Ogwedhi Health Center, chatted with Sheila Abuyu, who oversees H.I.V. care there.Nancy Adhiambo, a mother of five, learned she had H.I.V. during her third pregnancy. She started treatment but struggled to stay on the drugs as she moved around while leaving a chaotic relationship, and she couldn’t obtain medication consistently for her baby.That little girl, who is now 8, wasn’t tested for H.I.V. for years, even though she was often sick with pneumonia as a toddler. It wasn’t until last year, when Ms. Adhiambo found herself living down the street from a clinic in Migori town and joined a tightknit mothers’ group that she had all her children tested and learned that her third child was infected. So was her last-born, a 1-year-old. (Her two oldest and her fourth child were negative.)These days, the older daughter’s H.I.V. is well controlled, and so is Ms. Adhiambo’s. Her face folded into a pleased half-smile when the clinic director congratulated her on the girl’s low viral count.But when Ms. Adhiambo stopped by the pharmacy for the children’s drugs, she heard the same answer she had been given for weeks: The free pills were out of stock. She couldn’t afford the ones that were for sale in town, given that she earns at most a thousand shillings, about 10 U.S. dollars, each month as a hairdresser, she said, so she would divide her remaining tablets among the children.“Poverty complicates things,” she said bluntly. “We can only hope for the best.”

Some people who have long lived with the disease say they worry about living as a healthy person, while others worry about the obstacles to getting treatment.Terry Jackson lives a life dominated by sickle cell disease. The genetic disorder, in which misshapen red cells become wedged in blood vessels, causes him daily bone pain and lower back pain and has sent him to the hospital for pain treatment and life threatening emergencies for five decades. He has frequent transfusions of fresh blood.“You can’t escape it,” said Dr. Jackson, who owns a science communication business. “It is life-changing. It is each breath you take.”The disease has directed his every choice. It led him to get a Ph.D. in genetics from Duke University because he became fascinated with the science behind it. It is central to his identity.“I ask myself, ‘Who am I without sickle cell?’” Dr. Jackson said, adding, “it’s hard to even imagine what I would do, what would I be, if I don’t have it any more.”This year, Dr. Jackson and other people with sickle cell may have the option of finally living without the damage the disease causes. Two drug companies are seeking approval from the Food and Drug Administration for gene therapies that may provide what amounts to a cure. But the decision to take the medication — should it become available — it turns out, is not so simple.Some like Dr. Jackson worry about after a life adapted to their illness and are unsure of how to begin again as healthy people. Do they go back to school after dropping out because of their illness? Do they start looking for jobs after thinking that, with frequent hospitalizations because of sickle cell, they were unemployable? What if this new life is not so easy to enter?Others fear that the logistical complexities of gene therapies may imperil their ability to access them.These and other dilemmas illustrate an often hidden aspects of medical advances — a long awaited cure can be accompanied by trepidation.Sickle cell disease affects at least 100,000 people in the United States and millions worldwide. It mostly strikes Black and Hispanic or Latino people, but it also occurs in people with Mediterranean and Indian ancestors. People with the disease face searing pain, stroke, damage to tissues and organs and often death at an early age.Two gene therapy drugs, one from Bluebird Bio and the other by Vertex and CRISPR Therapeutics, have been in clinical trials. Both efforts reported that patients were freed of debilitating episodes of pain. Their blood was no longer flooded with misshapen red cells.Dr. Jackson was literally a poster child for the disease. He said he might reject a cure in part because sickle cell is so much a part of his identity that he can’t imagine life without it.Carlos Bernate for The New York Times“This is what science has been working toward for 50 or 60 years,” said Dr. Lewis Hsu, chief medical officer at the Sickle Cell Disease Association of America and director of the pediatric sickle cell program at the University of Illinois at Chicago.Sickle cell leads to a steady drip of costs over a lifetime, affecting caregivers as well as patients and often limiting the incomes of both because of time lost from work or an inability to work.One report examined what private insurance companies paid and found that the lifetime costs of sickle cell were $1.7 million, including $44,000 that patients paid out of pocket.That, patients and advocates said, does not begin to capture what sickle cell really costs. Ashley Valentine, co-founder of the national advocacy group Sick Cells, said she had to take three months off from work in 2016 to help her brother, Marqus, who had sickle cell. When he had a hip replacement in 2018, her father missed so much work to help care for Marqus that he accepted a layoff from his job. It affected her mother’s job, too.“And that’s just us,” she said.Marqus died in 2020, at age 36, from a stroke caused by sickle cell.While costs like the ones Ms. Valentine described are spread out over a lifetime, gene therapy must be paid for all at once. Concerns about the high price of the treatment worry many people with sickle cell and their families.The modified virus that delivers gene therapy is expected to cost at least $1 million, based on what other gene therapy vectors cost. But that is only part of the price.Treatment starts with intense chemotherapy in a hospital to wipe the bone marrow clean, leaving space for genetically modified red blood cells that result from the treatment. Patients then spend about a month in the hospital waiting for the modified cells to grow. After they are discharged, the patients are immunocompromised for about six months while their immune systems recover.Insurers are likely to pay for the part of the treatment that involves using a disabled virus to deliver the therapy. But whether they will pay for most of the chemo, hospitalization and other costs is uncertain. Patients worry about bills from hospitals and doctors. Even if it is mostly covered, co-payments can be an issue.Will wealthier people get the treatment while others look on longingly, patients ask?And, independent of the cost, how easy will it be for patients and family members who assist them to take off a month or more for the treatment, often traveling to distant cities with medical centers that can administer the treatment?Ashley Valentine, co-founder of the national advocacy group Sick Cells, in her parents’ home in Lisle, Ill. Her brother, Marqus, pictured directly above her, died in 2020 from a stroke caused by sickle cell.Mustafa Hussain for The New York TimesThat could be a deciding factor for Doris Polanco, 36. She hates having sickle cell. She suffered so much in winter because cold brought on pain crises that she moved to Tampa from New York in April 2021.“I couldn’t even go to the grocery store,” she said. “It was like I had to hibernate.”She would love to have gene therapy but recognizes that it will be difficult to suddenly become a healthy person. “It would be insanely hard,” she said. However, she added, “I would embrace it.”But she has other concerns, particularly about her 7- and 12-year-old daughters. The long hospitalization for gene therapy followed by months of recuperation would be hard on them, she said.“They are not babies, but they need me,” Ms. Polanco said.Patients ask when in the course of the disease is gene therapy needed. If they wait too long, the disease can lead to a stroke or permanent to damage organs and bones. But if the disease is mild and manageable, is it better to wait? André Marcel Harris, 33, who lives in Houston, decided that waiting is his best option.“I am not as sick as many others,” he said. “At this point, gene therapy is not part of the conversation.”Shamar Lewis, 20, who lives in Orlando, Fla., has several concerns — possible long term side effects of gene therapy, costs and the monthslong process of being treated and recovering.Still, sickle cell has been such a burden. He spent years of early adolescence unable to go to school because he was so sick — his school even sent teachers to his home. He has now finished high school and is interested in joining the military but has since learned that, with sickle cell, he would not be accepted. With gene therapy, “I would be able to truly live my life,” he told his mother, Carla Lewis.But what would that life be like?Without the disease, said Teonna Woolford, 31, a sickle cell patient and advocate who lives in Owings Mills, Md., patients “don’t know who they are.” Many worry, she said, about “trading one familiar issue — sickle cell — with something else and overall fear of the unknown.”A poem Marqus, Ms. Valentine’s brother, wrote on the back of a hospital cafeteria receipt during a stay in 2021.Mustafa Hussain for The New York TimesDr. Jackson shared that sentiment, saying that without sickle cell, “I’m an outsider, no longer part of this community.”Kevin Wake, 54, who lives in Kansas City, Mo., said sickle cell forced him to retire from his job in pharmaceutical sales and management and led him to think his days might be numbered. His two brothers died of the disease.He spends his time as an advocate for people with the condition. He’d like to have gene therapy but wonders if he’d be accepted — he’s had three strokes because of sickle cell. And he asks: If he were cured, could he get a full-time job after being absent from the work force for years? What sort of work would he do? He thinks he might like a job at a drug company that is developing sickle cell treatments, perhaps as a patient advocate if they are looking for such employees.A few people may reject the cure altogether. Dr. Jackson said he would in part because sickle cell is so much a part of his identity that he can’t imagine life without it. Others may reject it out of mistrust of the medical system.But there are also patients who cannot wait for gene therapy. Jimi Olaghere participated in the Vertex and Crispr trial 30 months ago, when he was 35. His life is transformed, he said.“The daily pain I used to face — literally round-the-clock pain — that’s gone,” he said.“Every day, I used to be bedridden,” he added. “I used to be so short of breath I couldn’t do any activity. Now I can’t stop.”Yet gene therapy cannot undo all the effects of sickle cell. Mr. Olaghere was left with residual permanent injuries from years with the disease, including damage to his hip.Like Dr. Jackson or Ms. Polanco, sickle cell shaped Mr. Olaghere’s most important life decisions. He chose a job in e-commerce because it gave him flexibility and allowed him to work at home. He moved from New Jersey to Atlanta to get away from cold winters.And he did experience “an identity crisis,” when he had to make a life without sickle cell, he said. But now all of his suffering except, he says, for “mental health challenges,” is gone.“It feels like a miracle,” Mr. Olaghere said.

Published7 hours agoShareclose panelShare pageCopy linkAbout sharingImage source, Getty ImagesBy Annabel Rackham and Elena BaileyBBC NewsReducing an antidepressant dose should be done in stages, with help from a medical professional, according to the National Institute for Health and Care Excellence (NICE).It says this helps manage withdrawal symptoms that can occur from the drugs.NICE has published new information that sets out how mental health care can be improved in England and Wales. A committee of experts says community care services should work with patients to agree a treatment plan.This includes assessing whether it is right for them to come off their medication and over what time period withdrawal should take place.Another suggestion is that extra attention should be paid to adults from minority ethnic backgrounds who have depression.It comes after NHS Digital data from 2021 showed that 57% of people from mixed, Black, Black British, Asian or Asian British family backgrounds completed a course of treatment for depression compared with 64% of people from a white family background. The suggestion is that mental health services should be delivered in a way that is culturally appropriate and that language barriers are also removed. ‘My anti-depressant withdrawal was worse than depression’Doctors warn of antidepressant withdrawalAccording to the NHS, antidepressant prescriptions reached an all-time high in 2022, with 8.3 million people taking them in England. Statistics also show about one in six adults aged 16 or over in the UK experienced some form of depression in the summer of 2021, with the rate remaining higher than before the coronavirus pandemic and lockdowns. ‘No one-size fits all approach’The recommendations are in addition to pre-existing ones on managing depression in adults, which were last updated in November 2021.NICE suggested then that people with mild depression should be offered behavioural therapy or group exercise before medication is discussed.Dr Paul Chrisp, who is in charge of NICE guidelines, said: “In many cases, people experience withdrawal symptoms, and the length of time it takes them to safely come off these drugs can vary, which is why our committee’s useful and useable statement for a staged withdrawal over time from these drugs is to be welcomed.If you are affected by any of the issues in this article you can find details of organisations that can help via the BBC Action Line.”But it should be stressed there is no one-size fits all approach to coming off antidepressants,” he added. In response to the proposals, Prof Allan Young from the Centre for Affective Disorders, Institute of Psychiatry, Psychology & Neuroscience said: “It makes complete sense that the guidelines for treating depression in adults – which were published in June last year- are followed. “Whether it can be delivered given the current state of the NHS is another question.”‘It was like a constant hangover times five’Image source, John JuniorJohn Junior, 34, started taking antidepressants in 2017 after being diagnosed with depression and generalised anxiety disorder.Gradually building up his dosage of sertraline, he says the drug “really did help” curb suicidal thoughts he had been having.However, he found the side effects unbearable.”I suffered from palpitations, which is a horrible side effect, and I was getting all sorts of headaches, migraines, more severe anxiety and stuff, even high blood pressure as well,” he told the BBC.”And then I’d be prescribed more medications to try and mask the other side effects I was experiencing.”It got to the point where I thought I was going to be fully dependent on antidepressants,” he says.During the coronavirus lockdown, he decided to come off the medication, but could not get through to his doctor.”The phone was always engaged – which made it really difficult.”I was experiencing more and more side effects and it just wasn’t working for me, my body reached its limit and I just knew I had to come off of them.”He says going “cold turkey” caused “sickness, headaches, raw anxiety, sweats and sleepless nights” and likened it to a “constant hangover times five”. John says he is coping well since coming off antidepressants and uses the gym and meditation to keep his mental health in check. He welcomes the new NICE guidance and says: “I think having an individual plan would be a great idea because it would give people that structure. And having that communication and reassurance from medical professionals would be great.” Stephen Buckley from the mental health charity Mind, says: “Medication helps some people, but it isn’t always right for others.”If you’re taking medication for your mental health, you might reach a point where you want to stop taking it. “We strongly suggest talking to your doctor or mental health team if you are thinking of withdrawing from your medication, you want to change medication, or you are experiencing withdrawal symptoms, so that you can be supported to come off or change your medication safely over time.” If you are affected by any of the issues in this article you can find details of organisations that can help via the BBC Action Line.More on this storyNearly half million more adults on antidepressants9 July 2022Doctors warn of antidepressant withdrawal30 May 2019NHS could give therapy before anti-depressants23 November 2021’My anti-depressant withdrawal was worse than depression’12 March 2020

Analyzing a person’s gene expression requires mapping their RNA landscape to a standard reference to gain insight into the degree to which genes are “turned on” and perform functions in the body. But researchers can run into issues when the reference does not provide enough information to allow for accurate mapping, an issue known as reference bias.
In a new paper published in the journal Nature Methods, researchers at UC Santa Cruz introduce the first-ever method for analyzing RNA sequencing data genome-wide using a “pantranscriptome,” which combines a transcriptome and a pangenome — a reference that contains genetic material from a cohort of diverse individuals, rather than just a single linear strand. A group of scientists led by UCSC Associate Professor of Biomolecular Engineering Benedict Paten have released a toolkit that allows researchers to map an individual’s RNA data to a much richer reference, addressing reference bias and leading to much more accurate mapping.
“This is pangenome plus transcriptome — that combination has never really been done before until now,” said Jordan Eizenga, the paper’s co-first author and a postdoctoral scholar in the UCSC Computational Genomics Lab. “This is the first time anyone has attempted to incorporate the pangenome as a standard feature of the RNA sequencing mapping.”
This tool will aid researchers around the world who are working to understand gene expression through RNA sequencing analysis. The tools are publicly available and can be accessed via Github.
“With this toolkit, we are employing this more diverse data that we can now get from the pangenome to improve the measurement of gene expression data, something that can widely vary between individuals,” Paten said. “The aim is to make the impact of this more diverse data felt on studies that are looking at gene expression, resulting in better analysis for cell models, organoid models, and other research applications.”
RNA’s most commonly recognized function is to translate DNA into proteins, but scientists now understand that the vast majority of RNA is noncoding and does not make proteins, but instead can play roles such as influencing cell structure or regulating genes. The entire RNA landscape is known collectively as the transcriptome, and mapping this allows researchers to better understand an individual’s gene expression.

The pantranscriptome builds on the emerging concept of “pangenomics” in the genomics field. Typically when evaluating an individual’s genomic data for variation, scientists compare the individual’s genome to that of a reference made up of a single linear strand of DNA bases. Using a pangenome allows researchers to compare an individual’s genome to that of a genetically diverse cohort of reference sequences all at once, sourced from individuals representing a diversity of biogeographic ancestry. This gives the scientists more points of comparison for which to better understand an individual’s genomic variation.
Mapping RNA sequencing data to understand gene expression can be difficult because the RNA sequences are spliced by cellular mechanisms, meaning one set of RNA data can come from non-connected areas of the genome, making it challenging to correctly align them to a reference. These splicing sites are not uniform across the human population, but vary between individuals. It is also difficult to know which haplotype the RNA comes from — whether the group of genes comes specifically from the set of chromosomes inherited from the individual’s mother, or the set inherited from the father.
But with the new pipeline of open source tools, the researchers can take the spliced segments of an individual’s RNA, map where they align on a pangenome, identify which haplotype the data belongs to, and analyze gene expression.
First, the pipeline identifies which areas of the genome the RNA sequencing data comes from, including the splice sites, and marks those points on the pangenome reference. Those marked points are then compared to a pantranscriptome consisting of haplotype-specific transcripts generated from the reference data contained within the pangenome. This step requires specialized, challenging algorithmic methods.
Finally, it generates estimates of levels of gene expression based on this comparison between the mapped data and the transcripts in the pantranscriptome, and identifies which haplotypes the genes come from.
“It’s definitely a very forward-looking study in that other genome-wide expression methods are not yet really utilizing pangenomes and haplotype information,” said Jonas Sibbesen, co-first author on the study and a former postdoctoral scholar in the UCSC Computational Genomics Lab who is now an assistant professor at the University of Copenhagen. “We’re now thinking ahead as to what pangenomics might additionally bring to the table in transcriptomic analyses.”
Going forward, the researchers are interested in further developing these tools to be useful for downstream informatics analysis, and tailoring the tools for the particularities of research on single-cell data. For now, the group hopes their new toolkit will serve to show how useful using pangenomics-derived analysis can be.
“We need to be able to explain to some researchers how a pangenome reference will benefit them,” Paten said. “This pipeline is really a first go at doing this for RNA, for functional data, for expression data.”

Powered by supermassive black holes swallowing matter in the centers of galaxies, active galactic nuclei are the most powerful compact steady sources of energy in the universe. The brightest active galactic nuclei have long been known to far outshine the combined light of the billions of stars in their host galaxies.
A new study indicates that scientists have substantially underestimated the energy output of these objects by not recognizing the extent to which their light is dimmed by dust.
“When there are intervening small particles along our line of sight, this makes things behind them look dimmer. We see this at sunset on any clear day when the sun looks fainter,” said Martin Gaskell, a research associate in astronomy and astrophysics at UC Santa Cruz.
Gaskell is lead author of a paper on the new findings published January 16 in Monthly Notices of the Royal Astronomical Society.
Although the possibility of dust dimming the light from active galactic nuclei has been recognized for a long time, the amount was controversial and was widely believed to be negligible, he said.
“We have shown that this is not the case and that the far ultraviolet light of a typical active galactic nucleus is dimmed by a large factor,” Gaskell said.

The team reached this conclusion by studying the reddening effect of dust on the light from one of the most well-studied active galactic nuclei, known as NGC 5548. Just as the Earth’s atmosphere makes the sun appear redder as well as dimmer at sunset, so dust in active galactic nuclei also makes them appear redder than they really are. The amount of reddening is related to the amount of dimming.
Scientists quantify the colors of something by measuring the ratios of the intensity of its light at different wavelengths. While we know what the unreddened color of the sun is, there has been much debate over the unreddened colors of the various types of emission from active galactic nuclei. This is because, although simple theories predict the intrinsic, unreddened colors, there were doubts about whether these simple theories applied to active galactic nuclei.
In the new study of NGC 5548, the UCSC researchers used seven different indicators of the amount of dust and found them all to be in good agreement. Furthermore, the dimming of NGC 5548 due to dust was found to be large, more than ten times the dimming caused by dust as we look out of our own galaxy, the Milky Way.
“The good agreement between the different indicators of the amount of reddening was a pleasant surprise,” said Gaskell. “It strongly supports simple theories of emission from active galactic nuclei. Exotic explanations of colors are not needed. This makes life simpler for researchers and is speeding up our understanding of what happens as black holes swallow material.”
The colors of NGC 5548 are typical of other active galactic nuclei, he said, which has wide-ranging implications. Because of the dimming effects of dust, active galactic nuclei are even more powerful than had been realized. The results imply that in the ultraviolet, where most of the energy is radiated, a typical active galactic nucleus is putting out an order of magnitude more energy than previously thought, Gaskell said.
Another implication, he said, is that active galactic nuclei are very similar, and what had hitherto been thought to be major fundamental differences between them are really just the consequences of different amounts of reddening by dust.
Gaskell’s coauthors — Frances Anderson (now at Harvey Mudd College), Sufia Birmingham (now at Princeton University), and Samhita Ghosh (now at UC Berkeley) — worked on this project as high school seniors participating in the UCSC Science Internship Program.

Researchers at the University of Waterloo have created a computational model to predict the growth of deadly brain tumours more accurately.
Glioblastoma multiforme (GBM) is a brain cancer with an average survival rate of only one year. It is difficult to treat due to its extremely dense core, rapid growth, and location in the brain. Estimating these tumours’ diffusivity and proliferation rate is useful for clinicians, but that information is hard to predict for an individual patient quickly and accurately.
Researchers at the University of Waterloo and the University of Toronto have partnered with St. Michael’s Hospital in Toronto to analyze MRI data from multiple GBM sufferers. They’re using machine learning to fully analyze a patient’s tumour, to better predict cancer progression.
Researchers analyzed two sets of MRIs from each of five anonymous patients suffering from GBM. The patients underwent extensive MRIs, waited several months, and then received a second set of MRIs. Because these patients, for undisclosed reasons, chose not to receive any treatment or intervention during this time, their MRIs provided the scientists with a unique opportunity to understand how GBM grows when left unchecked.
The researchers used a deep learning model to turn the MRI data into patient-specific parameter estimates that inform a predictive model for GBM growth. This technique was applied to patients’ and synthetic tumours, for which the true characteristics were known, enabling them to validate the model.
“We would have loved to do this analysis on a huge data set,” said Cameron Meaney, a PhD candidate in Applied Mathematics and the study’s lead researcher. “Based on the nature of the illness, however, that’s very challenging because there isn’t a long life expectancy, and people tend to start treatment. That’s why the opportunity to compare five untreated tumours was so rare — and valuable.”
Now that the scientists have a good model of how GBM grows untreated, their next step is to expand the model to include the effect of treatment on the tumours. Then the data set would increase from a handful of MRIs to thousands.
Meaney emphasizes that access to MRI data — and partnership between mathematicians and clinicians — can have huge impacts on patients going forward.
“The integration of quantitative analysis into healthcare is the future,” Meaney said.

New research finds that ice-sheet-wide collapse in West Antarctica isn’t inevitable: the pace of ice loss varies according to regional differences in atmosphere and ocean circulation.
An international team of researchers has combined satellite imagery and climate and ocean records to obtain the most detailed understanding yet of how the West Antarctic Ice Sheet — which contains enough ice to raise global sea level by 3.3 metres — is responding to climate change.
The researchers, from the University of Cambridge, the University of Edinburgh and the University of Washington, found that the pace and extent of ice destabilisation along West Antarctica’s coast varies according to differences in regional climate.
Their results, reported in the journal Nature Communications, show that while the West Antarctic Ice Sheet continues to retreat, the pace of retreat slowed across a vulnerable region of the coastline between 2003 and 2015. This slowdown was driven by changes in surrounding ocean temperature, which were in turn caused by variations in offshore wind conditions.
The marine-based West Antarctic Ice Sheet, home to the vast and unstable Pine Island and Thwaites glaciers, sits atop a landmass lying up to 2,500 metres below the surface of the ocean. Since the early 1990s, scientists have observed an abrupt acceleration in ice melting, retreat and speed in this area, which is attributed in part to human-induced climate change over the past century.
Other scientists have previously indicated that this type of response across a low-lying landmass could be the onset of an irreversible, ice-sheet-wide collapse called a marine ice sheet instability, which would continue independently of any further climatic influence.

“The idea that once a marine-based ice sheet passes a certain tipping point it will cause a runaway response has been widely reported,” said Dr Frazer Christie from Cambridge’s Scott Polar Research Institute, the paper’s lead author. “Despite this, questions remain about the extent to which ongoing changes in climate still regulate ice losses along the entire West Antarctic coastline.”
Using observations collected by an array of satellites, Christie and colleagues found pronounced regional variations in how the West Antarctic Ice Sheet has evolved since 2003 due to climate change, with the pace of retreat in the Amundsen Sea Sector having slowed significantly in comparison to the neighbouring and much accelerated Bellingshausen Sea Sector.
By analysing climate and ocean records, the researchers linked these regional differences to changes in the strength and direction of offshore surface winds.
In this part of Antarctica, the prevailing winds come from the west. When these westerly winds get stronger, they stir up warmer, saltier water from deep in the ocean, which reaches the Antarctic coastline and increases the rate of ice melt.
“But between 2003 and 2015 offshore of the Amundsen Sea Sector, the intensity of the prevailing westerly winds reduced,” said Christie. “This meant that the deeper, warmer water couldn’t intrude, and we saw a notable change in corresponding glacier behaviour along the region: a clear reduction in the rate of melt and ice-mass loss.”
So what caused these weaker winds and, by implication, reduced ice melt? The researchers found the primary cause was an unusual deepening of the Amundsen Sea Low pressure system, which led to less warm water intrusion. This system is the key atmospheric circulation pattern in the region, and its pressure centre location — near which changes in offshore wind strength are greatest — typically sits offshore of its namesake coast for most of the year.

Farther afield from this pressure centre, the researchers found that the accelerated response of the glaciers flowing from the Bellingshausen Sea Sector can be explained by relatively more unaltered winds, enabling more persistent ocean-driven melt by comparison.
Ultimately, the study illustrates the complexity of the competing ice, ocean and atmosphere interactions driving short-term changes across West Antarctica, and raises important questions about how quickly the icy continent will evolve in a warming world.
“Ocean and atmospheric forcing mechanisms still really, really matter in West Antarctica,” said co-author Professor Eric Steig from the University of Washington in Seattle. “That means that ice-sheet collapse is not inevitable. It depends on how climate changes over the next few decades, which we could influence in a positive way by reducing greenhouse gas emissions.”
The researchers stress that further work is needed to examine how important such mechanisms will be in the future amid a background of increasing marine ice sheet instability. Co-author Professor Robert Bingham from the University of Edinburgh is now working directly on Thwaites Glacier to understand how it is being affected by climate change.
“This study reinforces the urgent requirement to clarify how rapidly the most vulnerable regions of the West Antarctic Ice Sheet such as Thwaites Glacier will retreat, with global consequences for sea level rise,” said Bingham. “New data that we are currently acquiring from a traverse across Thwaites Glacier this January will directly address this goal.”
“There is an intimate link between the climate and how the ice is behaving,” said Christie. “We have the ability to mitigate West Antarctic ice losses — if we curb carbon emissions.”
The study was supported by the Carnegie Trust for the Universities of Scotland, the Scottish Alliance for Geoscience, Environment and Society (SAGES), the Prince Albert II of Monaco Foundation, the Natural Environment Research Council (NERC), part of UK Research and Innovation (UKRI), the US National Science Foundation, the joint UK NERC/US NSF International Thwaites Glacier Collaboration project and the European Space Agency (ESA).