Pediatrics

If you could go back in time 75 years and tell Dr. Sidney Farber, the developer of methotrexate for cancer therapy, that 21st-century medicine would utilize his specially designed drug more in rheumatology than oncology, he might be surprised. He might scratch his head even more, hearing of his drug sparking interest in still other medical fields, like cardiology.

But drug repurposing is not so uncommon. One classic example is aspirin. Once the most common pain medication and used also in rheumatology, aspirin now finds a range of applications, from colorectal cancer to the prevention of cardiovascular and cerebrovascular thrombosis. Minoxidil is another example, developed for hypertension but used today mostly to stop hair loss. Perhaps most ironic is thalidomide, utilized today for leprosy and multiple myeloma, yet actually contraindicated for its original application, nausea of pregnancy.

Courtesy NIH

Methotrexate, thus, has much in common with other medical treatments, and yet its origin story is as unique and as fascinating as the story of Dr. Farber himself. While this is a rheumatology article, it’s also a story about the origin of a particular rheumatologic treatment, and so the story of that origin will take us mostly through a discussion of hematologic malignancy and of the clinical researcher who dared search for a cure.

Born in 1903, in Buffalo, New York, third of fourteen children of Jewish immigrants from Poland, Dr. Farber grew up in a household that was crowded but academically rigorous. His father, Simon, routinely brought home textbooks, assigning each child a book to read and on which to write a report. His mother, Matilda, was as devoted as her husband to raising the children to succeed in their adopted new country. Upstairs, the children were permitted to speak Yiddish, but downstairs they were required to use only English and German.

As a teen, Dr. Farber lived through the 1918 influenza pandemic that killed at least 50 million people worldwide, including more than 2,000 Buffalonians. This probably helped motivate him to study medicine, but with antisemitism overt in the America of the early 1920s, securing admission to a U.S. medical school was close to impossible. So, in what now seems like the greatest of ironies, Dr. Farber began medical studies in Germany, then transferred for the second year to a U.S. program that seemed adequate – Harvard Medical School, from which he graduated in 1927. From there, he trained as a pathologist, focusing ultimately on pediatric pathology. But, frustrated by case after case of malignancy, whose young victims he’d often have to autopsy, Dr. Farber decided that he wanted to advance the pitiful state of cancer therapeutics, especially for hematologic malignancy.

This was a tall order in the 1930s and early 1940s, when cancer therapeutics consisted only of surgical resection and very primitive forms of radiation therapy. Applicable only to neoplasia that was localized, these options were useless against malignancies in the blood, like acute lymphoblastic leukemia (ALL), but by January 1948 there was at least one glimmer of hope. At that time, one patient with ALL, 2-year-old Robert Sandler, was too ill to join his twin brother Elliott for snow play outside their home in the Dorchester section of Boston. Diagnosed back in August, Robert had suffered multiple episodes of fever, anemia, and thrombocytopenia. His illness had enlarged his spleen dramatically and caused pathologic bone fractures with excruciating bone pain, and for a while he couldn’t walk because of pressure on his lower spinal cord. All of this was the result of uncontrolled mitosis and cell division of lymphoblasts, immature lymphocytes. By December, these out-of-control cells had elevated the boy’s white blood cell count to a peak of 70,000/mcL, more than six times the high end of the normal range (4,500-11,000/mcL). This had happened despite treatment with an experimental drug, developed at Boston Children’s Hospital by Dr. Farber and his team, working on the assumption that inhibition of folate metabolism should slow the growth of tumor cells. On Dec. 28, however, Dr. Farber had switched the child to a new drug with a chemical structure just slightly different from the other agent’s.

Merely another chemical modification in a series of attempts by the research team, the new drug, aminopterin, was not expected to do anything dramatic, but Dr. Farber and the team had come such a long way since the middle of 1947, when he’d actually done the opposite of what he was doing now. On the basis of British research from India showing folic acid deficiency as the basis of a common type of anemia in malnourished people, Dr. Farber had reasoned that children with leukemia, who also suffered from anemia, might also benefit from folic acid supplementation. Even without prior rodent testing, Dr. Farber had tried giving the nutrient to patients with ALL, a strategy made possible by the presence of a spectacular chemist working on folic acid synthesis at Farber’s own hospital to help combat folate deficiency. Born into a poor Brahmin family in India, the chemist, Dr. Yellapragada SubbaRow, had begun life with so much stacked against him as to appear even less likely during childhood than the young Dr. Farber to grow up to make major contributions to medicine. Going through childhood with death all around him, Dr. SubbaRow was motivated to study medicine, but getting into medical school had been an uphill fight, given his family’s economic difficulty. Knowing that he’d also face discrimination on account of his low status after receiving admission to a medical program, SubbaRow could have made things a bit easier for himself by living within the norms of the British Imperial system, but as a supporter of Mohandas Gandhi’s nationalist movement, he boycotted British goods. As a medical student, this meant doing things like wearing Indian-made surgical gloves, instead of the English products that were expected of the students. Such actions led Dr. SubbaRow to receive a kind of second-rate medical degree, rather than the prestigious MBBS.

The political situation also led Dr. SubbaRow to emigrate to the United States, where, ironically, his medical degree initially was taken less seriously than it had been taken in his British-occupied homeland. He thus worked in the capacity of a hospital night porter at Peter Bent Brigham Hospital (the future Brigham and Women’s Hospital), doing menial tasks like changing sheets to make ends meet. He studied, however, and made enough of an impression to gain admission to the same institution that also admitted Farber through the backdoor, Harvard Medical School. This launched him into a research career in which he not only would be instrumental in developing folate antagonists and other classes of drugs, but also would make him the codiscoverer of the role of creatine phosphate and ATP in cellular energy metabolism. Sadly, even after obtaining his top-notch American credentials and contributing through his research to what you might say is a good chunk of the biochemistry pathways that first year medical students memorize without ever learning who discovered them, Dr. SubbaRow still faced prejudice for the rest of his life, which turned out to last only until the age of 53. To add insult to injury, he is rarely remembered for his role.

Dr. Farber proceeded with the folic acid supplementation idea in patients with ALL, even though ALL caused a hypoproliferative anemia, whereas anemia from folate deficiency was megaloblastic, meaning that erythrocytes were produced but they were oversized and dysfunctional. Tragically, folic acid had accelerated the disease process in children with ALL, but the process of chemical experimentation aimed at synthesizing folate also produced some compounds that mimicked chemical precursors of folate in a way that made them antifolates, inhibitors of folate metabolism. If folic acid made lymphoblasts grow faster, Dr. Farber had reasoned that antifolates should inhibit their growth. He thus asked the chemistry lab to focus on folate inhibitors. Testing aminopterin, beginning with young Robert Sandler at the end of December, is what proved his hypothesis correct. By late January, aminopterin had brought the child’s WBC count down to the realm of 12,000, just slightly above normal, with symptoms and signs abating as well, and by February, the child could play with his twin brother. It was not a cure; malignant lymphoblasts still showed on microscopy of Robert’s blood. While he and some 15 other children whom Dr. Farber treated in this early trial would all succumb to ALL, they experienced remission lasting several months.

This was a big deal because the concept of chemotherapy was based only on serendipitous observations of WBC counts dropping in soldiers exposed to nitrogen mustard gas during World War I and during an incident in World War II, yet aminopterin had been designed from the ground up. Though difficult to synthesize in quantities, there was no reason for Dr. Farber’s team not to keep tweaking the drug, and so they did. Replacing one hydrogen atom with a methyl group, they turned it into methotrexate.

Proving easier to synthesize and less toxic, methotrexate would become a workhorse for chemotherapy over the next couple of decades, but the capability of both methotrexate and aminopterin to blunt the growth of white blood cells and other cells did not go unnoticed outside the realm of oncology. As early as the 1950s, dermatologists were using aminopterin to treat psoriasis. This led to the approval of methotrexate for psoriasis in 1972.

Meanwhile, like oncology, infectious diseases, aviation medicine, and so many other areas of practice, rheumatology had gotten a major boost from research stemming from World War II. During the war, Dr. Philip Hench of the Mayo Clinic developed cortisone, which pilots used to stay alert and energetic during trans-Atlantic flights. But it turned out that cortisone had a powerful immunosuppressive effect that dramatically improved rheumatoid arthritis, leading Dr. Hench to receive the Nobel Prize in Physiology or Medicine in 1950. By the end of the 1950s, however, the significant side effects of long-term corticosteroid therapy were very clear, so over the next few decades there was a major effort to develop different treatments for RA and other rheumatologic diseases.

Top on the list of such agents was methotrexate, developed for RA in part by Dr. Michael Weinblatt of Brigham and Women’s Hospital in Boston. In the 1980s, Dr. Weinblatt published the first clinical trial showing the benefits of methotrexate for RA patients. This has since developed into a standard treatment, noticeably different from the original malignancy application in that it is a low-dose regimen. Patients taking methotrexate for RA typically receive no more than 25 mg per week orally, and often much less. Rheumatology today includes expertise in keeping long-term methotrexate therapy safe by monitoring liver function and through other routine tests. The routine nature of the therapy has brought methotrexate to the point of beckoning in a realm that Dr. Farber might not have predicted in his wildest imagination: cardiology. This is on account of the growing appreciation of the inflammatory process in the pathophysiology of atherosclerotic heart disease.

Meanwhile, being an antimetabolite, harmful to rapidly dividing cells, the danger of methotrexate to the embryo and fetus was recognized early. This made methotrexate off-limits to pregnant women, yet it also has made the drug useful as an abortifacient. Though not as good for medication abortion in unwanted but thriving pregnancies, where mifepristone/misoprostol has become the regimen of choice, methotrexate has become a workhorse in other obstetrical settings, such as for ending ectopic pregnancy.

Looking at the present and into the future, the potential for this very old medication looks wide open, as if it could go in any direction, so let’s wind up the discussion with the thought that we may be in for some surprises. Rather than jumping deeply into any rheumatologic issue, we spent most of this article weaving through other medical issues, but does this not make today’s story fairly analogous to rheumatology itself?

Dr. Warmflash is a physician from Portland, Ore. He reported no conflicts of interest.

This story was updated 2/10/2023.

A version of this article first appeared on Medscape.com.

If you could go back in time 75 years and tell Dr. Sidney Farber, the developer of methotrexate for cancer therapy, that 21st-century medicine would utilize his specially designed drug more in rheumatology than oncology, he might be surprised. He might scratch his head even more, hearing of his drug sparking interest in still other medical fields, like cardiology.

But drug repurposing is not so uncommon. One classic example is aspirin. Once the most common pain medication and used also in rheumatology, aspirin now finds a range of applications, from colorectal cancer to the prevention of cardiovascular and cerebrovascular thrombosis. Minoxidil is another example, developed for hypertension but used today mostly to stop hair loss. Perhaps most ironic is thalidomide, utilized today for leprosy and multiple myeloma, yet actually contraindicated for its original application, nausea of pregnancy.

Courtesy NIH

Methotrexate, thus, has much in common with other medical treatments, and yet its origin story is as unique and as fascinating as the story of Dr. Farber himself. While this is a rheumatology article, it’s also a story about the origin of a particular rheumatologic treatment, and so the story of that origin will take us mostly through a discussion of hematologic malignancy and of the clinical researcher who dared search for a cure.

Born in 1903, in Buffalo, New York, third of fourteen children of Jewish immigrants from Poland, Dr. Farber grew up in a household that was crowded but academically rigorous. His father, Simon, routinely brought home textbooks, assigning each child a book to read and on which to write a report. His mother, Matilda, was as devoted as her husband to raising the children to succeed in their adopted new country. Upstairs, the children were permitted to speak Yiddish, but downstairs they were required to use only English and German.

As a teen, Dr. Farber lived through the 1918 influenza pandemic that killed at least 50 million people worldwide, including more than 2,000 Buffalonians. This probably helped motivate him to study medicine, but with antisemitism overt in the America of the early 1920s, securing admission to a U.S. medical school was close to impossible. So, in what now seems like the greatest of ironies, Dr. Farber began medical studies in Germany, then transferred for the second year to a U.S. program that seemed adequate – Harvard Medical School, from which he graduated in 1927. From there, he trained as a pathologist, focusing ultimately on pediatric pathology. But, frustrated by case after case of malignancy, whose young victims he’d often have to autopsy, Dr. Farber decided that he wanted to advance the pitiful state of cancer therapeutics, especially for hematologic malignancy.

This was a tall order in the 1930s and early 1940s, when cancer therapeutics consisted only of surgical resection and very primitive forms of radiation therapy. Applicable only to neoplasia that was localized, these options were useless against malignancies in the blood, like acute lymphoblastic leukemia (ALL), but by January 1948 there was at least one glimmer of hope. At that time, one patient with ALL, 2-year-old Robert Sandler, was too ill to join his twin brother Elliott for snow play outside their home in the Dorchester section of Boston. Diagnosed back in August, Robert had suffered multiple episodes of fever, anemia, and thrombocytopenia. His illness had enlarged his spleen dramatically and caused pathologic bone fractures with excruciating bone pain, and for a while he couldn’t walk because of pressure on his lower spinal cord. All of this was the result of uncontrolled mitosis and cell division of lymphoblasts, immature lymphocytes. By December, these out-of-control cells had elevated the boy’s white blood cell count to a peak of 70,000/mcL, more than six times the high end of the normal range (4,500-11,000/mcL). This had happened despite treatment with an experimental drug, developed at Boston Children’s Hospital by Dr. Farber and his team, working on the assumption that inhibition of folate metabolism should slow the growth of tumor cells. On Dec. 28, however, Dr. Farber had switched the child to a new drug with a chemical structure just slightly different from the other agent’s.

Merely another chemical modification in a series of attempts by the research team, the new drug, aminopterin, was not expected to do anything dramatic, but Dr. Farber and the team had come such a long way since the middle of 1947, when he’d actually done the opposite of what he was doing now. On the basis of British research from India showing folic acid deficiency as the basis of a common type of anemia in malnourished people, Dr. Farber had reasoned that children with leukemia, who also suffered from anemia, might also benefit from folic acid supplementation. Even without prior rodent testing, Dr. Farber had tried giving the nutrient to patients with ALL, a strategy made possible by the presence of a spectacular chemist working on folic acid synthesis at Farber’s own hospital to help combat folate deficiency. Born into a poor Brahmin family in India, the chemist, Dr. Yellapragada SubbaRow, had begun life with so much stacked against him as to appear even less likely during childhood than the young Dr. Farber to grow up to make major contributions to medicine. Going through childhood with death all around him, Dr. SubbaRow was motivated to study medicine, but getting into medical school had been an uphill fight, given his family’s economic difficulty. Knowing that he’d also face discrimination on account of his low status after receiving admission to a medical program, SubbaRow could have made things a bit easier for himself by living within the norms of the British Imperial system, but as a supporter of Mohandas Gandhi’s nationalist movement, he boycotted British goods. As a medical student, this meant doing things like wearing Indian-made surgical gloves, instead of the English products that were expected of the students. Such actions led Dr. SubbaRow to receive a kind of second-rate medical degree, rather than the prestigious MBBS.

The political situation also led Dr. SubbaRow to emigrate to the United States, where, ironically, his medical degree initially was taken less seriously than it had been taken in his British-occupied homeland. He thus worked in the capacity of a hospital night porter at Peter Bent Brigham Hospital (the future Brigham and Women’s Hospital), doing menial tasks like changing sheets to make ends meet. He studied, however, and made enough of an impression to gain admission to the same institution that also admitted Farber through the backdoor, Harvard Medical School. This launched him into a research career in which he not only would be instrumental in developing folate antagonists and other classes of drugs, but also would make him the codiscoverer of the role of creatine phosphate and ATP in cellular energy metabolism. Sadly, even after obtaining his top-notch American credentials and contributing through his research to what you might say is a good chunk of the biochemistry pathways that first year medical students memorize without ever learning who discovered them, Dr. SubbaRow still faced prejudice for the rest of his life, which turned out to last only until the age of 53. To add insult to injury, he is rarely remembered for his role.

Dr. Farber proceeded with the folic acid supplementation idea in patients with ALL, even though ALL caused a hypoproliferative anemia, whereas anemia from folate deficiency was megaloblastic, meaning that erythrocytes were produced but they were oversized and dysfunctional. Tragically, folic acid had accelerated the disease process in children with ALL, but the process of chemical experimentation aimed at synthesizing folate also produced some compounds that mimicked chemical precursors of folate in a way that made them antifolates, inhibitors of folate metabolism. If folic acid made lymphoblasts grow faster, Dr. Farber had reasoned that antifolates should inhibit their growth. He thus asked the chemistry lab to focus on folate inhibitors. Testing aminopterin, beginning with young Robert Sandler at the end of December, is what proved his hypothesis correct. By late January, aminopterin had brought the child’s WBC count down to the realm of 12,000, just slightly above normal, with symptoms and signs abating as well, and by February, the child could play with his twin brother. It was not a cure; malignant lymphoblasts still showed on microscopy of Robert’s blood. While he and some 15 other children whom Dr. Farber treated in this early trial would all succumb to ALL, they experienced remission lasting several months.

This was a big deal because the concept of chemotherapy was based only on serendipitous observations of WBC counts dropping in soldiers exposed to nitrogen mustard gas during World War I and during an incident in World War II, yet aminopterin had been designed from the ground up. Though difficult to synthesize in quantities, there was no reason for Dr. Farber’s team not to keep tweaking the drug, and so they did. Replacing one hydrogen atom with a methyl group, they turned it into methotrexate.

Proving easier to synthesize and less toxic, methotrexate would become a workhorse for chemotherapy over the next couple of decades, but the capability of both methotrexate and aminopterin to blunt the growth of white blood cells and other cells did not go unnoticed outside the realm of oncology. As early as the 1950s, dermatologists were using aminopterin to treat psoriasis. This led to the approval of methotrexate for psoriasis in 1972.

Meanwhile, like oncology, infectious diseases, aviation medicine, and so many other areas of practice, rheumatology had gotten a major boost from research stemming from World War II. During the war, Dr. Philip Hench of the Mayo Clinic developed cortisone, which pilots used to stay alert and energetic during trans-Atlantic flights. But it turned out that cortisone had a powerful immunosuppressive effect that dramatically improved rheumatoid arthritis, leading Dr. Hench to receive the Nobel Prize in Physiology or Medicine in 1950. By the end of the 1950s, however, the significant side effects of long-term corticosteroid therapy were very clear, so over the next few decades there was a major effort to develop different treatments for RA and other rheumatologic diseases.

Top on the list of such agents was methotrexate, developed for RA in part by Dr. Michael Weinblatt of Brigham and Women’s Hospital in Boston. In the 1980s, Dr. Weinblatt published the first clinical trial showing the benefits of methotrexate for RA patients. This has since developed into a standard treatment, noticeably different from the original malignancy application in that it is a low-dose regimen. Patients taking methotrexate for RA typically receive no more than 25 mg per week orally, and often much less. Rheumatology today includes expertise in keeping long-term methotrexate therapy safe by monitoring liver function and through other routine tests. The routine nature of the therapy has brought methotrexate to the point of beckoning in a realm that Dr. Farber might not have predicted in his wildest imagination: cardiology. This is on account of the growing appreciation of the inflammatory process in the pathophysiology of atherosclerotic heart disease.

Meanwhile, being an antimetabolite, harmful to rapidly dividing cells, the danger of methotrexate to the embryo and fetus was recognized early. This made methotrexate off-limits to pregnant women, yet it also has made the drug useful as an abortifacient. Though not as good for medication abortion in unwanted but thriving pregnancies, where mifepristone/misoprostol has become the regimen of choice, methotrexate has become a workhorse in other obstetrical settings, such as for ending ectopic pregnancy.

Looking at the present and into the future, the potential for this very old medication looks wide open, as if it could go in any direction, so let’s wind up the discussion with the thought that we may be in for some surprises. Rather than jumping deeply into any rheumatologic issue, we spent most of this article weaving through other medical issues, but does this not make today’s story fairly analogous to rheumatology itself?

Dr. Warmflash is a physician from Portland, Ore. He reported no conflicts of interest.

This story was updated 2/10/2023.

A version of this article first appeared on Medscape.com.

If you could go back in time 75 years and tell Dr. Sidney Farber, the developer of methotrexate for cancer therapy, that 21st-century medicine would utilize his specially designed drug more in rheumatology than oncology, he might be surprised. He might scratch his head even more, hearing of his drug sparking interest in still other medical fields, like cardiology.

But drug repurposing is not so uncommon. One classic example is aspirin. Once the most common pain medication and used also in rheumatology, aspirin now finds a range of applications, from colorectal cancer to the prevention of cardiovascular and cerebrovascular thrombosis. Minoxidil is another example, developed for hypertension but used today mostly to stop hair loss. Perhaps most ironic is thalidomide, utilized today for leprosy and multiple myeloma, yet actually contraindicated for its original application, nausea of pregnancy.

Courtesy NIH

Methotrexate, thus, has much in common with other medical treatments, and yet its origin story is as unique and as fascinating as the story of Dr. Farber himself. While this is a rheumatology article, it’s also a story about the origin of a particular rheumatologic treatment, and so the story of that origin will take us mostly through a discussion of hematologic malignancy and of the clinical researcher who dared search for a cure.

Born in 1903, in Buffalo, New York, third of fourteen children of Jewish immigrants from Poland, Dr. Farber grew up in a household that was crowded but academically rigorous. His father, Simon, routinely brought home textbooks, assigning each child a book to read and on which to write a report. His mother, Matilda, was as devoted as her husband to raising the children to succeed in their adopted new country. Upstairs, the children were permitted to speak Yiddish, but downstairs they were required to use only English and German.

As a teen, Dr. Farber lived through the 1918 influenza pandemic that killed at least 50 million people worldwide, including more than 2,000 Buffalonians. This probably helped motivate him to study medicine, but with antisemitism overt in the America of the early 1920s, securing admission to a U.S. medical school was close to impossible. So, in what now seems like the greatest of ironies, Dr. Farber began medical studies in Germany, then transferred for the second year to a U.S. program that seemed adequate – Harvard Medical School, from which he graduated in 1927. From there, he trained as a pathologist, focusing ultimately on pediatric pathology. But, frustrated by case after case of malignancy, whose young victims he’d often have to autopsy, Dr. Farber decided that he wanted to advance the pitiful state of cancer therapeutics, especially for hematologic malignancy.

This was a tall order in the 1930s and early 1940s, when cancer therapeutics consisted only of surgical resection and very primitive forms of radiation therapy. Applicable only to neoplasia that was localized, these options were useless against malignancies in the blood, like acute lymphoblastic leukemia (ALL), but by January 1948 there was at least one glimmer of hope. At that time, one patient with ALL, 2-year-old Robert Sandler, was too ill to join his twin brother Elliott for snow play outside their home in the Dorchester section of Boston. Diagnosed back in August, Robert had suffered multiple episodes of fever, anemia, and thrombocytopenia. His illness had enlarged his spleen dramatically and caused pathologic bone fractures with excruciating bone pain, and for a while he couldn’t walk because of pressure on his lower spinal cord. All of this was the result of uncontrolled mitosis and cell division of lymphoblasts, immature lymphocytes. By December, these out-of-control cells had elevated the boy’s white blood cell count to a peak of 70,000/mcL, more than six times the high end of the normal range (4,500-11,000/mcL). This had happened despite treatment with an experimental drug, developed at Boston Children’s Hospital by Dr. Farber and his team, working on the assumption that inhibition of folate metabolism should slow the growth of tumor cells. On Dec. 28, however, Dr. Farber had switched the child to a new drug with a chemical structure just slightly different from the other agent’s.

Merely another chemical modification in a series of attempts by the research team, the new drug, aminopterin, was not expected to do anything dramatic, but Dr. Farber and the team had come such a long way since the middle of 1947, when he’d actually done the opposite of what he was doing now. On the basis of British research from India showing folic acid deficiency as the basis of a common type of anemia in malnourished people, Dr. Farber had reasoned that children with leukemia, who also suffered from anemia, might also benefit from folic acid supplementation. Even without prior rodent testing, Dr. Farber had tried giving the nutrient to patients with ALL, a strategy made possible by the presence of a spectacular chemist working on folic acid synthesis at Farber’s own hospital to help combat folate deficiency. Born into a poor Brahmin family in India, the chemist, Dr. Yellapragada SubbaRow, had begun life with so much stacked against him as to appear even less likely during childhood than the young Dr. Farber to grow up to make major contributions to medicine. Going through childhood with death all around him, Dr. SubbaRow was motivated to study medicine, but getting into medical school had been an uphill fight, given his family’s economic difficulty. Knowing that he’d also face discrimination on account of his low status after receiving admission to a medical program, SubbaRow could have made things a bit easier for himself by living within the norms of the British Imperial system, but as a supporter of Mohandas Gandhi’s nationalist movement, he boycotted British goods. As a medical student, this meant doing things like wearing Indian-made surgical gloves, instead of the English products that were expected of the students. Such actions led Dr. SubbaRow to receive a kind of second-rate medical degree, rather than the prestigious MBBS.

The political situation also led Dr. SubbaRow to emigrate to the United States, where, ironically, his medical degree initially was taken less seriously than it had been taken in his British-occupied homeland. He thus worked in the capacity of a hospital night porter at Peter Bent Brigham Hospital (the future Brigham and Women’s Hospital), doing menial tasks like changing sheets to make ends meet. He studied, however, and made enough of an impression to gain admission to the same institution that also admitted Farber through the backdoor, Harvard Medical School. This launched him into a research career in which he not only would be instrumental in developing folate antagonists and other classes of drugs, but also would make him the codiscoverer of the role of creatine phosphate and ATP in cellular energy metabolism. Sadly, even after obtaining his top-notch American credentials and contributing through his research to what you might say is a good chunk of the biochemistry pathways that first year medical students memorize without ever learning who discovered them, Dr. SubbaRow still faced prejudice for the rest of his life, which turned out to last only until the age of 53. To add insult to injury, he is rarely remembered for his role.

Dr. Farber proceeded with the folic acid supplementation idea in patients with ALL, even though ALL caused a hypoproliferative anemia, whereas anemia from folate deficiency was megaloblastic, meaning that erythrocytes were produced but they were oversized and dysfunctional. Tragically, folic acid had accelerated the disease process in children with ALL, but the process of chemical experimentation aimed at synthesizing folate also produced some compounds that mimicked chemical precursors of folate in a way that made them antifolates, inhibitors of folate metabolism. If folic acid made lymphoblasts grow faster, Dr. Farber had reasoned that antifolates should inhibit their growth. He thus asked the chemistry lab to focus on folate inhibitors. Testing aminopterin, beginning with young Robert Sandler at the end of December, is what proved his hypothesis correct. By late January, aminopterin had brought the child’s WBC count down to the realm of 12,000, just slightly above normal, with symptoms and signs abating as well, and by February, the child could play with his twin brother. It was not a cure; malignant lymphoblasts still showed on microscopy of Robert’s blood. While he and some 15 other children whom Dr. Farber treated in this early trial would all succumb to ALL, they experienced remission lasting several months.

This was a big deal because the concept of chemotherapy was based only on serendipitous observations of WBC counts dropping in soldiers exposed to nitrogen mustard gas during World War I and during an incident in World War II, yet aminopterin had been designed from the ground up. Though difficult to synthesize in quantities, there was no reason for Dr. Farber’s team not to keep tweaking the drug, and so they did. Replacing one hydrogen atom with a methyl group, they turned it into methotrexate.

Proving easier to synthesize and less toxic, methotrexate would become a workhorse for chemotherapy over the next couple of decades, but the capability of both methotrexate and aminopterin to blunt the growth of white blood cells and other cells did not go unnoticed outside the realm of oncology. As early as the 1950s, dermatologists were using aminopterin to treat psoriasis. This led to the approval of methotrexate for psoriasis in 1972.

Meanwhile, like oncology, infectious diseases, aviation medicine, and so many other areas of practice, rheumatology had gotten a major boost from research stemming from World War II. During the war, Dr. Philip Hench of the Mayo Clinic developed cortisone, which pilots used to stay alert and energetic during trans-Atlantic flights. But it turned out that cortisone had a powerful immunosuppressive effect that dramatically improved rheumatoid arthritis, leading Dr. Hench to receive the Nobel Prize in Physiology or Medicine in 1950. By the end of the 1950s, however, the significant side effects of long-term corticosteroid therapy were very clear, so over the next few decades there was a major effort to develop different treatments for RA and other rheumatologic diseases.

Top on the list of such agents was methotrexate, developed for RA in part by Dr. Michael Weinblatt of Brigham and Women’s Hospital in Boston. In the 1980s, Dr. Weinblatt published the first clinical trial showing the benefits of methotrexate for RA patients. This has since developed into a standard treatment, noticeably different from the original malignancy application in that it is a low-dose regimen. Patients taking methotrexate for RA typically receive no more than 25 mg per week orally, and often much less. Rheumatology today includes expertise in keeping long-term methotrexate therapy safe by monitoring liver function and through other routine tests. The routine nature of the therapy has brought methotrexate to the point of beckoning in a realm that Dr. Farber might not have predicted in his wildest imagination: cardiology. This is on account of the growing appreciation of the inflammatory process in the pathophysiology of atherosclerotic heart disease.

Meanwhile, being an antimetabolite, harmful to rapidly dividing cells, the danger of methotrexate to the embryo and fetus was recognized early. This made methotrexate off-limits to pregnant women, yet it also has made the drug useful as an abortifacient. Though not as good for medication abortion in unwanted but thriving pregnancies, where mifepristone/misoprostol has become the regimen of choice, methotrexate has become a workhorse in other obstetrical settings, such as for ending ectopic pregnancy.

Looking at the present and into the future, the potential for this very old medication looks wide open, as if it could go in any direction, so let’s wind up the discussion with the thought that we may be in for some surprises. Rather than jumping deeply into any rheumatologic issue, we spent most of this article weaving through other medical issues, but does this not make today’s story fairly analogous to rheumatology itself?

Dr. Warmflash is a physician from Portland, Ore. He reported no conflicts of interest.

This story was updated 2/10/2023.

A version of this article first appeared on Medscape.com.

General pediatricians and a multidisciplinary team of specialists agreed most of the time on which children should be diagnosed with autism spectrum disorder (ASD), data from a new study suggest.

But when it came to ruling out ASD, the agreement rate was much lower.

The study by Melanie Penner, MSc, MD, with the Autism Research Centre at Bloorview Research Institute, Toronto, and colleagues found that 89% of the time when a physician determined a child had ASD, the multidisciplinary team agreed. But when a pediatrician thought a child did not have ASD, the multidisciplinary team agreed only 60% of the time. The study was published in JAMA Network Open.

Multidisciplinary team model can’t keep up with demand

The findings are important as many guidelines recommend multidisciplinary teams (MDTs) for all ASD diagnostic assessment. However, the resources for this model can’t meet the demand of children needing a diagnosis and can lead to long waits for ASD therapies.

In Canada, the researchers note, the average wait time from referral to receipt of ASD diagnosis has been reported as 7 months and “has likely lengthened since the COVID-19 pandemic.”

Jennifer Gerdts, PhD, an attending psychologist at the Seattle Children’s Autism Center, said in an interview that the wait there for diagnosis in children older than 4 is “multiple years,” a length of time that’s common across the United States. Meanwhile, in many states families can’t access services without a diagnosis.

Expanding capacity with diagnoses by general pediatricians may improve access, but the diagnostic accuracy is critical.

Dr. Gerdts, who was not part of the study, said this research is “hugely important in the work that is under way to build community capacity for diagnostic evaluation.”

She said this study shows that not all diagnoses need the resources of a multiple-disciplinary team and that “pediatricians can do it, too, and they can do it pretty accurately.” Dr. Gerdts evaluates children for autism and helps train pediatricians to make diagnoses.
 

Pediatricians, specialist team completed blinded assessments

The 17 pediatricians in the study and the specialist team independently completed blinded assessment and each recorded a decision on whether the child had ASD. The prospective diagnostic study was conducted in a specialist assessment center in Toronto and in general pediatrician practices in Ontario from June 2016 to March 2020.

Children were younger than 5.5 years, did not have an ASD diagnosis and were referred because there was a development concern. The pediatricians referred 106 children (75% boys; average age, 3.5 years). More than half (57%) of the participating children were from minority racial and ethnic groups.

The children were randomly assigned to two groups: One included children who had their MDT visits before their pediatrician assessment and the other group included those who had their MDT visits after their pediatrician assessment.

The MDT diagnosed more than two-thirds of the children (68%) with ASD.

Sensitivity and specificity of the pediatrician assessments, compared with that of the specialist team, were 0.75 (95% confidence interval, 0.67-0.83) and 0.79 (95% CI, 0.62-0.91), respectively.
 

A look at pediatricians’ accuracy

Pediatricians reported the decisions they would have made had the child not been in the study.

• In 69% of the true-positive cases, pediatricians would have given an ASD diagnosis.
• In 44% of true-negative cases, they would have told the family the child did not have autism; in 30% of those case, they would give alternative diagnoses (most commonly ADHD and language delay).
• The pediatrician would have diagnosed ASD in only one of the seven false-positive cases and would refer those patients to a subspecialist 71% of the time.
• In false-negative cases, the pediatrician would incorrectly tell the family the child does not have autism 44% of the time.

Regarding the false-negative cases, the authors wrote, “more caution is needed for pediatricians when definitively ruling out ASD, which might result in diagnostic delays.”
 

Confidence is key

Physician confidence was also correlated with accuracy.

The authors wrote: “Among true-positive cases (MDT and pediatrician agree the child has ASD), the pediatrician was certain or very certain 80% of the time (43 cases) and the MDT was certain or very certain 96% of the time (52 cases). As such, if pediatricians conferred ASD diagnoses when feeling certain or very certain, they would make 46 correct diagnoses and 2 incorrect diagnoses.”

The high accuracy of diagnosis when physicians are confident suggests “listening to that sense of certainty is important,” Dr. Gerdts said. Conversely, these numbers show when a physician is uncertain about diagnosing ASD, they should listen to that instinct, too, and refer.

The results of the study support having general pediatricians diagnose and move forward with their patients when the signs of ASD are more definitive, saving the less-certain cases for the more resource-intensive teams to diagnose. Many states are moving toward that “tiered” system, Dr. Gerdts said.

“For many, and in fact most children, general pediatricians are pretty accurate when making an autism diagnosis,” she said.

“Let’s get [general pediatricians] confident in recognizing when this is outside their skill and ability level,” she said. “If you’re not sure, it is better to refer them on than to misdiagnose them.”

The important missing piece she said is how to support them “so they don’t feel pressure to make that call,” Dr. Gerdts said.

This project was funded by a grant from the Bloorview Research Institute, a grant from the Canadian Institutes of Health Research and a grant from the Canadian Institutes of Health. Three coauthors consult for and receive grants from several pharmaceutical companies and other organizations. Dr. Gerdts declared no relevant financial relationships.

General pediatricians and a multidisciplinary team of specialists agreed most of the time on which children should be diagnosed with autism spectrum disorder (ASD), data from a new study suggest.

But when it came to ruling out ASD, the agreement rate was much lower.

The study by Melanie Penner, MSc, MD, with the Autism Research Centre at Bloorview Research Institute, Toronto, and colleagues found that 89% of the time when a physician determined a child had ASD, the multidisciplinary team agreed. But when a pediatrician thought a child did not have ASD, the multidisciplinary team agreed only 60% of the time. The study was published in JAMA Network Open.

Multidisciplinary team model can’t keep up with demand

The findings are important as many guidelines recommend multidisciplinary teams (MDTs) for all ASD diagnostic assessment. However, the resources for this model can’t meet the demand of children needing a diagnosis and can lead to long waits for ASD therapies.

In Canada, the researchers note, the average wait time from referral to receipt of ASD diagnosis has been reported as 7 months and “has likely lengthened since the COVID-19 pandemic.”

Jennifer Gerdts, PhD, an attending psychologist at the Seattle Children’s Autism Center, said in an interview that the wait there for diagnosis in children older than 4 is “multiple years,” a length of time that’s common across the United States. Meanwhile, in many states families can’t access services without a diagnosis.

Expanding capacity with diagnoses by general pediatricians may improve access, but the diagnostic accuracy is critical.

Dr. Gerdts, who was not part of the study, said this research is “hugely important in the work that is under way to build community capacity for diagnostic evaluation.”

She said this study shows that not all diagnoses need the resources of a multiple-disciplinary team and that “pediatricians can do it, too, and they can do it pretty accurately.” Dr. Gerdts evaluates children for autism and helps train pediatricians to make diagnoses.
 

Pediatricians, specialist team completed blinded assessments

The 17 pediatricians in the study and the specialist team independently completed blinded assessment and each recorded a decision on whether the child had ASD. The prospective diagnostic study was conducted in a specialist assessment center in Toronto and in general pediatrician practices in Ontario from June 2016 to March 2020.

Children were younger than 5.5 years, did not have an ASD diagnosis and were referred because there was a development concern. The pediatricians referred 106 children (75% boys; average age, 3.5 years). More than half (57%) of the participating children were from minority racial and ethnic groups.

The children were randomly assigned to two groups: One included children who had their MDT visits before their pediatrician assessment and the other group included those who had their MDT visits after their pediatrician assessment.

The MDT diagnosed more than two-thirds of the children (68%) with ASD.

Sensitivity and specificity of the pediatrician assessments, compared with that of the specialist team, were 0.75 (95% confidence interval, 0.67-0.83) and 0.79 (95% CI, 0.62-0.91), respectively.
 

A look at pediatricians’ accuracy

Pediatricians reported the decisions they would have made had the child not been in the study.

• In 69% of the true-positive cases, pediatricians would have given an ASD diagnosis.
• In 44% of true-negative cases, they would have told the family the child did not have autism; in 30% of those case, they would give alternative diagnoses (most commonly ADHD and language delay).
• The pediatrician would have diagnosed ASD in only one of the seven false-positive cases and would refer those patients to a subspecialist 71% of the time.
• In false-negative cases, the pediatrician would incorrectly tell the family the child does not have autism 44% of the time.

Regarding the false-negative cases, the authors wrote, “more caution is needed for pediatricians when definitively ruling out ASD, which might result in diagnostic delays.”
 

Confidence is key

Physician confidence was also correlated with accuracy.

The authors wrote: “Among true-positive cases (MDT and pediatrician agree the child has ASD), the pediatrician was certain or very certain 80% of the time (43 cases) and the MDT was certain or very certain 96% of the time (52 cases). As such, if pediatricians conferred ASD diagnoses when feeling certain or very certain, they would make 46 correct diagnoses and 2 incorrect diagnoses.”

The high accuracy of diagnosis when physicians are confident suggests “listening to that sense of certainty is important,” Dr. Gerdts said. Conversely, these numbers show when a physician is uncertain about diagnosing ASD, they should listen to that instinct, too, and refer.

The results of the study support having general pediatricians diagnose and move forward with their patients when the signs of ASD are more definitive, saving the less-certain cases for the more resource-intensive teams to diagnose. Many states are moving toward that “tiered” system, Dr. Gerdts said.

“For many, and in fact most children, general pediatricians are pretty accurate when making an autism diagnosis,” she said.

“Let’s get [general pediatricians] confident in recognizing when this is outside their skill and ability level,” she said. “If you’re not sure, it is better to refer them on than to misdiagnose them.”

The important missing piece she said is how to support them “so they don’t feel pressure to make that call,” Dr. Gerdts said.

This project was funded by a grant from the Bloorview Research Institute, a grant from the Canadian Institutes of Health Research and a grant from the Canadian Institutes of Health. Three coauthors consult for and receive grants from several pharmaceutical companies and other organizations. Dr. Gerdts declared no relevant financial relationships.

General pediatricians and a multidisciplinary team of specialists agreed most of the time on which children should be diagnosed with autism spectrum disorder (ASD), data from a new study suggest.

But when it came to ruling out ASD, the agreement rate was much lower.

The study by Melanie Penner, MSc, MD, with the Autism Research Centre at Bloorview Research Institute, Toronto, and colleagues found that 89% of the time when a physician determined a child had ASD, the multidisciplinary team agreed. But when a pediatrician thought a child did not have ASD, the multidisciplinary team agreed only 60% of the time. The study was published in JAMA Network Open.

Multidisciplinary team model can’t keep up with demand

The findings are important as many guidelines recommend multidisciplinary teams (MDTs) for all ASD diagnostic assessment. However, the resources for this model can’t meet the demand of children needing a diagnosis and can lead to long waits for ASD therapies.

In Canada, the researchers note, the average wait time from referral to receipt of ASD diagnosis has been reported as 7 months and “has likely lengthened since the COVID-19 pandemic.”

Jennifer Gerdts, PhD, an attending psychologist at the Seattle Children’s Autism Center, said in an interview that the wait there for diagnosis in children older than 4 is “multiple years,” a length of time that’s common across the United States. Meanwhile, in many states families can’t access services without a diagnosis.

Expanding capacity with diagnoses by general pediatricians may improve access, but the diagnostic accuracy is critical.

Dr. Gerdts, who was not part of the study, said this research is “hugely important in the work that is under way to build community capacity for diagnostic evaluation.”

She said this study shows that not all diagnoses need the resources of a multiple-disciplinary team and that “pediatricians can do it, too, and they can do it pretty accurately.” Dr. Gerdts evaluates children for autism and helps train pediatricians to make diagnoses.
 

Pediatricians, specialist team completed blinded assessments

The 17 pediatricians in the study and the specialist team independently completed blinded assessment and each recorded a decision on whether the child had ASD. The prospective diagnostic study was conducted in a specialist assessment center in Toronto and in general pediatrician practices in Ontario from June 2016 to March 2020.

Children were younger than 5.5 years, did not have an ASD diagnosis and were referred because there was a development concern. The pediatricians referred 106 children (75% boys; average age, 3.5 years). More than half (57%) of the participating children were from minority racial and ethnic groups.

The children were randomly assigned to two groups: One included children who had their MDT visits before their pediatrician assessment and the other group included those who had their MDT visits after their pediatrician assessment.

The MDT diagnosed more than two-thirds of the children (68%) with ASD.

Sensitivity and specificity of the pediatrician assessments, compared with that of the specialist team, were 0.75 (95% confidence interval, 0.67-0.83) and 0.79 (95% CI, 0.62-0.91), respectively.
 

A look at pediatricians’ accuracy

Pediatricians reported the decisions they would have made had the child not been in the study.

• In 69% of the true-positive cases, pediatricians would have given an ASD diagnosis.
• In 44% of true-negative cases, they would have told the family the child did not have autism; in 30% of those case, they would give alternative diagnoses (most commonly ADHD and language delay).
• The pediatrician would have diagnosed ASD in only one of the seven false-positive cases and would refer those patients to a subspecialist 71% of the time.
• In false-negative cases, the pediatrician would incorrectly tell the family the child does not have autism 44% of the time.

Regarding the false-negative cases, the authors wrote, “more caution is needed for pediatricians when definitively ruling out ASD, which might result in diagnostic delays.”
 

Confidence is key

Physician confidence was also correlated with accuracy.

The authors wrote: “Among true-positive cases (MDT and pediatrician agree the child has ASD), the pediatrician was certain or very certain 80% of the time (43 cases) and the MDT was certain or very certain 96% of the time (52 cases). As such, if pediatricians conferred ASD diagnoses when feeling certain or very certain, they would make 46 correct diagnoses and 2 incorrect diagnoses.”

The high accuracy of diagnosis when physicians are confident suggests “listening to that sense of certainty is important,” Dr. Gerdts said. Conversely, these numbers show when a physician is uncertain about diagnosing ASD, they should listen to that instinct, too, and refer.

The results of the study support having general pediatricians diagnose and move forward with their patients when the signs of ASD are more definitive, saving the less-certain cases for the more resource-intensive teams to diagnose. Many states are moving toward that “tiered” system, Dr. Gerdts said.

“For many, and in fact most children, general pediatricians are pretty accurate when making an autism diagnosis,” she said.

“Let’s get [general pediatricians] confident in recognizing when this is outside their skill and ability level,” she said. “If you’re not sure, it is better to refer them on than to misdiagnose them.”

The important missing piece she said is how to support them “so they don’t feel pressure to make that call,” Dr. Gerdts said.

This project was funded by a grant from the Bloorview Research Institute, a grant from the Canadian Institutes of Health Research and a grant from the Canadian Institutes of Health. Three coauthors consult for and receive grants from several pharmaceutical companies and other organizations. Dr. Gerdts declared no relevant financial relationships.

The Food and Drug Administration has cleared the Tidepool Loop, a mobile application for use with compatible continuous glucose monitors (CGMs) and insulin pumps to enable automated insulin delivery.

Indicated for people with type 1 diabetes ages 6 years and up, the app algorithm was developed by the diabetes startup Tidepool, which already hosts a cloud-based platform for users to download and review data from different glucose meters, insulin pumps, and CGM systems. The Tidepool Loop project arose from patient-led, open-source initiatives to enable interoperability between the devices.

Olivier Le Moal/Getty Images

“The [FDA] authorization of the Tidepool Loop is a huge win for the type 1 diabetes (T1D) community and is a vital step towards a world where people with T1D can choose the pump, CGM, and algorithm that are best for them – and have all three work together seamlessly,” Aaron Kowalski, PhD, CEO of the advocacy organization JDRF, said in a statement.

JDRF helped support preclinical and clinical research in the development of the Loop algorithm, along with The Leona M. and Harry B. Helmsley Charitable Trust, the Tullman Foundation, and partnerships with device makers and donations from the T1D community.

Available by prescription only, the Tidepool app is for single patient use. It works with designated “integrated CGMs” and “alternate controller enabled pumps” to automatically increase, decrease, or suspend insulin delivery, based on the glucose readings and predicted values. The app can also recommend correction doses, which the user can confirm.

According to an FDA statement:“Tidepool Loop’s algorithm technology is designed to be compatible with other individual interoperable devices that meet prespecified acceptance criteria set forth in a validation and integration plan provided by the sponsor and cleared by the FDA as part of the premarket submission.”

Tidepool is finalizing agreements with the various device manufacturers “to create a seamless experience for both physicians prescribing Tidepool Loop and the patients using it,” according to a company statement.

Tidepool’s initial launch device partners have not yet been announced, but the company “has a development partnership with Dexcom and other yet-to-be-named medical device companies for future inclusion of their components with the Tidepool Loop platform,” the statement says.

A version of this article first appeared on Medscape.com.

The Food and Drug Administration has cleared the Tidepool Loop, a mobile application for use with compatible continuous glucose monitors (CGMs) and insulin pumps to enable automated insulin delivery.

Indicated for people with type 1 diabetes ages 6 years and up, the app algorithm was developed by the diabetes startup Tidepool, which already hosts a cloud-based platform for users to download and review data from different glucose meters, insulin pumps, and CGM systems. The Tidepool Loop project arose from patient-led, open-source initiatives to enable interoperability between the devices.

Olivier Le Moal/Getty Images

“The [FDA] authorization of the Tidepool Loop is a huge win for the type 1 diabetes (T1D) community and is a vital step towards a world where people with T1D can choose the pump, CGM, and algorithm that are best for them – and have all three work together seamlessly,” Aaron Kowalski, PhD, CEO of the advocacy organization JDRF, said in a statement.

JDRF helped support preclinical and clinical research in the development of the Loop algorithm, along with The Leona M. and Harry B. Helmsley Charitable Trust, the Tullman Foundation, and partnerships with device makers and donations from the T1D community.

Available by prescription only, the Tidepool app is for single patient use. It works with designated “integrated CGMs” and “alternate controller enabled pumps” to automatically increase, decrease, or suspend insulin delivery, based on the glucose readings and predicted values. The app can also recommend correction doses, which the user can confirm.

According to an FDA statement:“Tidepool Loop’s algorithm technology is designed to be compatible with other individual interoperable devices that meet prespecified acceptance criteria set forth in a validation and integration plan provided by the sponsor and cleared by the FDA as part of the premarket submission.”

Tidepool is finalizing agreements with the various device manufacturers “to create a seamless experience for both physicians prescribing Tidepool Loop and the patients using it,” according to a company statement.

Tidepool’s initial launch device partners have not yet been announced, but the company “has a development partnership with Dexcom and other yet-to-be-named medical device companies for future inclusion of their components with the Tidepool Loop platform,” the statement says.

A version of this article first appeared on Medscape.com.

The Food and Drug Administration has cleared the Tidepool Loop, a mobile application for use with compatible continuous glucose monitors (CGMs) and insulin pumps to enable automated insulin delivery.

Indicated for people with type 1 diabetes ages 6 years and up, the app algorithm was developed by the diabetes startup Tidepool, which already hosts a cloud-based platform for users to download and review data from different glucose meters, insulin pumps, and CGM systems. The Tidepool Loop project arose from patient-led, open-source initiatives to enable interoperability between the devices.

Olivier Le Moal/Getty Images

“The [FDA] authorization of the Tidepool Loop is a huge win for the type 1 diabetes (T1D) community and is a vital step towards a world where people with T1D can choose the pump, CGM, and algorithm that are best for them – and have all three work together seamlessly,” Aaron Kowalski, PhD, CEO of the advocacy organization JDRF, said in a statement.

JDRF helped support preclinical and clinical research in the development of the Loop algorithm, along with The Leona M. and Harry B. Helmsley Charitable Trust, the Tullman Foundation, and partnerships with device makers and donations from the T1D community.

Available by prescription only, the Tidepool app is for single patient use. It works with designated “integrated CGMs” and “alternate controller enabled pumps” to automatically increase, decrease, or suspend insulin delivery, based on the glucose readings and predicted values. The app can also recommend correction doses, which the user can confirm.

According to an FDA statement:“Tidepool Loop’s algorithm technology is designed to be compatible with other individual interoperable devices that meet prespecified acceptance criteria set forth in a validation and integration plan provided by the sponsor and cleared by the FDA as part of the premarket submission.”

Tidepool is finalizing agreements with the various device manufacturers “to create a seamless experience for both physicians prescribing Tidepool Loop and the patients using it,” according to a company statement.

Tidepool’s initial launch device partners have not yet been announced, but the company “has a development partnership with Dexcom and other yet-to-be-named medical device companies for future inclusion of their components with the Tidepool Loop platform,” the statement says.

A version of this article first appeared on Medscape.com.

Approximately two out of three children with autism spectrum disorder (ASD) do not have concurrent intellectual disability, according to a population study of ASD trends.

Intellectual functioning remains the best predictor of functional outcomes in kids with ASD, and missing those with no cognitive impairment (ASD-N) can prevent intervention and affect future achievement.

Furthermore, while the study found that ASD-N increased among all demographic subgroups from 2000 to 2016, it also observed widespread health disparities in identifying ASD-N, especially in Black, Hispanic, and underprivileged children.

“ASD is a major public health concern and prevalence estimates are likely to continue to rise as disparities are reduced and ASD identification is improved,” wrote researchers led by Josephine Shenouda, DrPH, MS, of Rutgers School of Public Health in Piscataway, N.J., in Pediatrics .

The study period saw a surprising 500% increase in the prevalence of ASD-N and a 200% increase in the prevalence of cognitive impairment–associated ASD-I , with higher rates across all sex, race, ethnicity, and socioeconomic subgroups. The five- and twofold respective increases are consistent with previous research.

“To a large degree, the rise in autism estimates has been driven by individuals without intellectual disability,” Dr. Shenouda said in an interview. “The best way to address increasing autism and to affect disparities in autism identification is through universal autism screening during the toddler period. And different metrics of functional outcomes need to be developed to understand the expression of autism better.”

Her group had previously seen autism estimates of approximately 1% in 2000 rise to 3% by 2016 but had noted variations, with some communities exceeding 5% for autism estimates. “That led to the question of why, and we saw that in areas with high estimates, we are identifying more children with autism without intellectual disability,” she said. “We wanted to know if the increase over time was equally distributed among children with autism with and without intellectual disability.”
 

A study in disparities

The cross-sectional study examined data from active ASD surveillance by the CDC’s Autism and Developmental Disabilities Monitoring Network in 8-year-olds residing in the New York/New Jersey Metropolitan Area. Overall, 4,661 children were identified with ASD, with ASD-I affecting 1,505 (32.3%), and ASD-N affecting 2,764 (59.3%). Non-Hispanic Black children who were affected numbered 946 (20.3%), while 1,230 (26.4%) were Hispanic, and 2,114 (45.4%) were non-Hispanic White.

Notably, Black children were 30% less likely to be identified with ASD-N compared with White children, and children residing in affluent areas were 80% more likely to be identified with ASD-N versus those in underserved areas. Furthermore, a greater proportion of children with ASD-I resided in vulnerable areas compared with their counterparts with ASD-N.

While males had a higher prevalence compared with females regardless of intellectual disability status, male-to-female ratios were slightly lower among ASD-I compared with ASD-N cases.

Commenting on the study but not involved in it, Barbara J. Howard, MD, an assistant professor of medicine at Johns Hopkins University, Baltimore, said the increasing gap in identifying ASD-N according to race, ethnicity, and socioeconomic status measures probably reflects greater parental awareness of ASD and access to diagnostic services in White families and those of higher socioeconomic status. “There were no racial, ethnicity, or socioeconomic status differences in the prevalence of the more obvious and impairing ASD-I in the sample, but its prevalence was also increasing over this period,” she said.

Although the greater recognition of the less impairing ASD-N is important for optimal outcomes through intervention, the increasing discrepancies mean that more children generally and more marginalized children specifically are not being diagnosed or served. “There should be no differences in prevalence by these characteristics,” Dr. Howard said. “The striking inequity for non-White children and those of lower socioeconomic status in being diagnosed with ASD-N and thus qualifying for intervention that could improve their long-term functioning is likely also compounded by service, educational, and social disadvantages they may experience.”

In light of these disparities, an accompanying editorial by Emily Hotez, PhD, of the University of California, Los Angeles, and Lindsay Shea, DrPH, of the A.J. Drexel Autism Institute at Drexel University, Philadelphia, argues that social determinants of health (SDOH) should be prioritized in the public health surveillance of autism since these factors potentially contribute to the general underdiagnosis of autism in minority groups and merit more attention from pediatricians. While SDOH affects many nonautistic conditions, it may be even more important for families dealing with the stressors and isolation associated with autism, the commentators said. “Our commentary speaks to the utility of increasing SDOH surveillance in improving our understanding of autistic individuals’ needs, experiences, and priorities on a population level,” Dr. Hotez said in an interview. She added that integrating SDOH surveillance into pediatricians’ workflows will lead to improvements in clinical practice and patient care in the long term.

“Specifically, increased uptake of universal SDOH screening and referral practices will allow pediatricians to more proactively link autistic children and families, particularly those from marginalized groups, with much-needed health-promoting services and supports.” She cautioned, however, that while most providers believe universal SDOH screening is important, fewer report that screening is feasible or feel prepared to address families’ social needs when they are identified.

This study was supported by the Centers for Disease Control and Prevention and the National Institutes of Health/National Institute of Environmental Health Sciences. The authors had no conflicts of interest to disclose. The commentators had no potential conflicts of interest to disclose. Dr. Howard disclosed no competing interests relevant to her comments.
 

Approximately two out of three children with autism spectrum disorder (ASD) do not have concurrent intellectual disability, according to a population study of ASD trends.

Intellectual functioning remains the best predictor of functional outcomes in kids with ASD, and missing those with no cognitive impairment (ASD-N) can prevent intervention and affect future achievement.

Furthermore, while the study found that ASD-N increased among all demographic subgroups from 2000 to 2016, it also observed widespread health disparities in identifying ASD-N, especially in Black, Hispanic, and underprivileged children.

“ASD is a major public health concern and prevalence estimates are likely to continue to rise as disparities are reduced and ASD identification is improved,” wrote researchers led by Josephine Shenouda, DrPH, MS, of Rutgers School of Public Health in Piscataway, N.J., in Pediatrics .

The study period saw a surprising 500% increase in the prevalence of ASD-N and a 200% increase in the prevalence of cognitive impairment–associated ASD-I , with higher rates across all sex, race, ethnicity, and socioeconomic subgroups. The five- and twofold respective increases are consistent with previous research.

“To a large degree, the rise in autism estimates has been driven by individuals without intellectual disability,” Dr. Shenouda said in an interview. “The best way to address increasing autism and to affect disparities in autism identification is through universal autism screening during the toddler period. And different metrics of functional outcomes need to be developed to understand the expression of autism better.”

Her group had previously seen autism estimates of approximately 1% in 2000 rise to 3% by 2016 but had noted variations, with some communities exceeding 5% for autism estimates. “That led to the question of why, and we saw that in areas with high estimates, we are identifying more children with autism without intellectual disability,” she said. “We wanted to know if the increase over time was equally distributed among children with autism with and without intellectual disability.”
 

A study in disparities

The cross-sectional study examined data from active ASD surveillance by the CDC’s Autism and Developmental Disabilities Monitoring Network in 8-year-olds residing in the New York/New Jersey Metropolitan Area. Overall, 4,661 children were identified with ASD, with ASD-I affecting 1,505 (32.3%), and ASD-N affecting 2,764 (59.3%). Non-Hispanic Black children who were affected numbered 946 (20.3%), while 1,230 (26.4%) were Hispanic, and 2,114 (45.4%) were non-Hispanic White.

Notably, Black children were 30% less likely to be identified with ASD-N compared with White children, and children residing in affluent areas were 80% more likely to be identified with ASD-N versus those in underserved areas. Furthermore, a greater proportion of children with ASD-I resided in vulnerable areas compared with their counterparts with ASD-N.

While males had a higher prevalence compared with females regardless of intellectual disability status, male-to-female ratios were slightly lower among ASD-I compared with ASD-N cases.

Commenting on the study but not involved in it, Barbara J. Howard, MD, an assistant professor of medicine at Johns Hopkins University, Baltimore, said the increasing gap in identifying ASD-N according to race, ethnicity, and socioeconomic status measures probably reflects greater parental awareness of ASD and access to diagnostic services in White families and those of higher socioeconomic status. “There were no racial, ethnicity, or socioeconomic status differences in the prevalence of the more obvious and impairing ASD-I in the sample, but its prevalence was also increasing over this period,” she said.

Although the greater recognition of the less impairing ASD-N is important for optimal outcomes through intervention, the increasing discrepancies mean that more children generally and more marginalized children specifically are not being diagnosed or served. “There should be no differences in prevalence by these characteristics,” Dr. Howard said. “The striking inequity for non-White children and those of lower socioeconomic status in being diagnosed with ASD-N and thus qualifying for intervention that could improve their long-term functioning is likely also compounded by service, educational, and social disadvantages they may experience.”

In light of these disparities, an accompanying editorial by Emily Hotez, PhD, of the University of California, Los Angeles, and Lindsay Shea, DrPH, of the A.J. Drexel Autism Institute at Drexel University, Philadelphia, argues that social determinants of health (SDOH) should be prioritized in the public health surveillance of autism since these factors potentially contribute to the general underdiagnosis of autism in minority groups and merit more attention from pediatricians. While SDOH affects many nonautistic conditions, it may be even more important for families dealing with the stressors and isolation associated with autism, the commentators said. “Our commentary speaks to the utility of increasing SDOH surveillance in improving our understanding of autistic individuals’ needs, experiences, and priorities on a population level,” Dr. Hotez said in an interview. She added that integrating SDOH surveillance into pediatricians’ workflows will lead to improvements in clinical practice and patient care in the long term.

“Specifically, increased uptake of universal SDOH screening and referral practices will allow pediatricians to more proactively link autistic children and families, particularly those from marginalized groups, with much-needed health-promoting services and supports.” She cautioned, however, that while most providers believe universal SDOH screening is important, fewer report that screening is feasible or feel prepared to address families’ social needs when they are identified.

This study was supported by the Centers for Disease Control and Prevention and the National Institutes of Health/National Institute of Environmental Health Sciences. The authors had no conflicts of interest to disclose. The commentators had no potential conflicts of interest to disclose. Dr. Howard disclosed no competing interests relevant to her comments.
 

Approximately two out of three children with autism spectrum disorder (ASD) do not have concurrent intellectual disability, according to a population study of ASD trends.

Intellectual functioning remains the best predictor of functional outcomes in kids with ASD, and missing those with no cognitive impairment (ASD-N) can prevent intervention and affect future achievement.

Furthermore, while the study found that ASD-N increased among all demographic subgroups from 2000 to 2016, it also observed widespread health disparities in identifying ASD-N, especially in Black, Hispanic, and underprivileged children.

“ASD is a major public health concern and prevalence estimates are likely to continue to rise as disparities are reduced and ASD identification is improved,” wrote researchers led by Josephine Shenouda, DrPH, MS, of Rutgers School of Public Health in Piscataway, N.J., in Pediatrics .

The study period saw a surprising 500% increase in the prevalence of ASD-N and a 200% increase in the prevalence of cognitive impairment–associated ASD-I , with higher rates across all sex, race, ethnicity, and socioeconomic subgroups. The five- and twofold respective increases are consistent with previous research.

“To a large degree, the rise in autism estimates has been driven by individuals without intellectual disability,” Dr. Shenouda said in an interview. “The best way to address increasing autism and to affect disparities in autism identification is through universal autism screening during the toddler period. And different metrics of functional outcomes need to be developed to understand the expression of autism better.”

Her group had previously seen autism estimates of approximately 1% in 2000 rise to 3% by 2016 but had noted variations, with some communities exceeding 5% for autism estimates. “That led to the question of why, and we saw that in areas with high estimates, we are identifying more children with autism without intellectual disability,” she said. “We wanted to know if the increase over time was equally distributed among children with autism with and without intellectual disability.”
 

A study in disparities

The cross-sectional study examined data from active ASD surveillance by the CDC’s Autism and Developmental Disabilities Monitoring Network in 8-year-olds residing in the New York/New Jersey Metropolitan Area. Overall, 4,661 children were identified with ASD, with ASD-I affecting 1,505 (32.3%), and ASD-N affecting 2,764 (59.3%). Non-Hispanic Black children who were affected numbered 946 (20.3%), while 1,230 (26.4%) were Hispanic, and 2,114 (45.4%) were non-Hispanic White.

Notably, Black children were 30% less likely to be identified with ASD-N compared with White children, and children residing in affluent areas were 80% more likely to be identified with ASD-N versus those in underserved areas. Furthermore, a greater proportion of children with ASD-I resided in vulnerable areas compared with their counterparts with ASD-N.

While males had a higher prevalence compared with females regardless of intellectual disability status, male-to-female ratios were slightly lower among ASD-I compared with ASD-N cases.

Commenting on the study but not involved in it, Barbara J. Howard, MD, an assistant professor of medicine at Johns Hopkins University, Baltimore, said the increasing gap in identifying ASD-N according to race, ethnicity, and socioeconomic status measures probably reflects greater parental awareness of ASD and access to diagnostic services in White families and those of higher socioeconomic status. “There were no racial, ethnicity, or socioeconomic status differences in the prevalence of the more obvious and impairing ASD-I in the sample, but its prevalence was also increasing over this period,” she said.

Although the greater recognition of the less impairing ASD-N is important for optimal outcomes through intervention, the increasing discrepancies mean that more children generally and more marginalized children specifically are not being diagnosed or served. “There should be no differences in prevalence by these characteristics,” Dr. Howard said. “The striking inequity for non-White children and those of lower socioeconomic status in being diagnosed with ASD-N and thus qualifying for intervention that could improve their long-term functioning is likely also compounded by service, educational, and social disadvantages they may experience.”

In light of these disparities, an accompanying editorial by Emily Hotez, PhD, of the University of California, Los Angeles, and Lindsay Shea, DrPH, of the A.J. Drexel Autism Institute at Drexel University, Philadelphia, argues that social determinants of health (SDOH) should be prioritized in the public health surveillance of autism since these factors potentially contribute to the general underdiagnosis of autism in minority groups and merit more attention from pediatricians. While SDOH affects many nonautistic conditions, it may be even more important for families dealing with the stressors and isolation associated with autism, the commentators said. “Our commentary speaks to the utility of increasing SDOH surveillance in improving our understanding of autistic individuals’ needs, experiences, and priorities on a population level,” Dr. Hotez said in an interview. She added that integrating SDOH surveillance into pediatricians’ workflows will lead to improvements in clinical practice and patient care in the long term.

“Specifically, increased uptake of universal SDOH screening and referral practices will allow pediatricians to more proactively link autistic children and families, particularly those from marginalized groups, with much-needed health-promoting services and supports.” She cautioned, however, that while most providers believe universal SDOH screening is important, fewer report that screening is feasible or feel prepared to address families’ social needs when they are identified.

This study was supported by the Centers for Disease Control and Prevention and the National Institutes of Health/National Institute of Environmental Health Sciences. The authors had no conflicts of interest to disclose. The commentators had no potential conflicts of interest to disclose. Dr. Howard disclosed no competing interests relevant to her comments.
 

Watching a screen more than an hour a day as a toddler is directly linked with poorer communication and daily living skills at age 4, but outdoor play may lessen some of the effects, new research suggests.

The results point to outdoor play as a potential targeted intervention to counter suboptimal brain development in young children who are watching screens at increasingly younger ages.

The findings were published online in JAMA Pediatrics.

The researchers first investigated whether higher screen time (more than 1 hour a day on a device or watching television) at age 2 years is associated with neurodevelopmental outcomes at age 4.

They found the 885 children in the sample from the Japanese Hamamatsu Birth Cohort Study for Mothers and Children who had more screen time had lower scores on communication and daily living skills than children who watched less than an hour a day.

Scores were based on the Vineland Adaptive Behavior Scale according to parent responses to questions. The children included were born between December 2007 and March 2012 and were followed from 18 months to 4 years.

After finding the connection between screen time and lower scores, the researchers investigated whether outdoor play (at least 30 minutes a day) introduced at a 2 years and 8 months made a difference. They considered 6 or 7 days per week frequent outdoor play.
 

Outdoor play mitigated poorer daily living scores

The researchers found that the outdoor play intervention mitigated 18% of the association between high screen time and lower daily living scores but did not mitigate the lower communication scores.

They also found that more screen time at age 2 was significantly linked with infrequent outdoor play at age 32 months (odds ratio, 2.03; 95% confidence interval, 1.48-2.76).

The associations were consistent after taking into account factors including a child’s sex, parental education, and any autism spectrum disorder symptoms at age 18 months.

The authors noted that neurodevelopment concerns with screen use are particularly troubling as the age for use is getting younger.

A recent meta-analysis found that 75% of children younger than 2 use or watch screens, even though guidelines recommend against any screen time before 2.

In addition, the “COVID-19 pandemic led to children having more screen time, less outdoor play, and less physical activity, putting them at potentially greater risk for neurodevelopmental problems,” the authors noted.

“What is concerning is that data show screen time has not decreased after seclusion measures were lifted,” they added.
 

Proven benefits for outdoor play

Jennifer Cross, MD,* assistant professor and section chief for developmental pediatrics at Weill Cornell Medicine, New York, who was not part of the study, said the mitigation properties of outdoor play were something she hadn’t seen before but the concept makes sense.

“The overwhelming evidence is that screen time is not helpful for young children under the age of 2,” she said.

Outdoor play, on the other hand, has proven benefits.

“Physical activity has been shown to be good for physical and mental health so there’s no reason to believe it wouldn’t be good for 2-and-a-half-year olds,” Dr. Cross said. “It’s also good for developmental health. You want them to be engaged in imaginative play and be interactive.”

“[Outdoor play] gets them away from screens and gives them an opportunity to experience another environment and work on their motor skills and motor planning,” she added. “Exercise will change, briefly, the way our brains process information.”

Dr. Cross added that a lot of motor skills are involved in daily living skills, such as feeding, dressing, and toileting.

Screen time is increasing

The authors acknowledged that screen time may be underestimated by parents. They also noted that they did not have access to what children were watching on the screens.

“This should have been collected because the effect of high screen time differs depending on the type of program,” the authors wrote.

They added that children born in the 2020s may have been exposed to more screen time than the children reared in the early 2010s in this study.

Dr. Cross said screen use in the 2020s may be higher than estimated here and higher in certain populations globally, so it’s not easy to tell if the intervention in this study would have the same mitigating effect on a real-world population.

However, she said, the effect of outdoor play is always going to be helpful for brain development and there’s no downside.

“Exercise is just as important for little kids as it is for grown-ups,” she said.

The authors reported no relevant financial disclosures. Dr. Cross reported no relevant financial disclosures.

*Dr. Jennifer Cross is the correct name, not Dr. Jennifer Frost. The correction was made on Jan. 27, 2023.

Watching a screen more than an hour a day as a toddler is directly linked with poorer communication and daily living skills at age 4, but outdoor play may lessen some of the effects, new research suggests.

The results point to outdoor play as a potential targeted intervention to counter suboptimal brain development in young children who are watching screens at increasingly younger ages.

The findings were published online in JAMA Pediatrics.

The researchers first investigated whether higher screen time (more than 1 hour a day on a device or watching television) at age 2 years is associated with neurodevelopmental outcomes at age 4.

They found the 885 children in the sample from the Japanese Hamamatsu Birth Cohort Study for Mothers and Children who had more screen time had lower scores on communication and daily living skills than children who watched less than an hour a day.

Scores were based on the Vineland Adaptive Behavior Scale according to parent responses to questions. The children included were born between December 2007 and March 2012 and were followed from 18 months to 4 years.

After finding the connection between screen time and lower scores, the researchers investigated whether outdoor play (at least 30 minutes a day) introduced at a 2 years and 8 months made a difference. They considered 6 or 7 days per week frequent outdoor play.
 

Outdoor play mitigated poorer daily living scores

The researchers found that the outdoor play intervention mitigated 18% of the association between high screen time and lower daily living scores but did not mitigate the lower communication scores.

They also found that more screen time at age 2 was significantly linked with infrequent outdoor play at age 32 months (odds ratio, 2.03; 95% confidence interval, 1.48-2.76).

The associations were consistent after taking into account factors including a child’s sex, parental education, and any autism spectrum disorder symptoms at age 18 months.

The authors noted that neurodevelopment concerns with screen use are particularly troubling as the age for use is getting younger.

A recent meta-analysis found that 75% of children younger than 2 use or watch screens, even though guidelines recommend against any screen time before 2.

In addition, the “COVID-19 pandemic led to children having more screen time, less outdoor play, and less physical activity, putting them at potentially greater risk for neurodevelopmental problems,” the authors noted.

“What is concerning is that data show screen time has not decreased after seclusion measures were lifted,” they added.
 

Proven benefits for outdoor play

Jennifer Cross, MD,* assistant professor and section chief for developmental pediatrics at Weill Cornell Medicine, New York, who was not part of the study, said the mitigation properties of outdoor play were something she hadn’t seen before but the concept makes sense.

“The overwhelming evidence is that screen time is not helpful for young children under the age of 2,” she said.

Outdoor play, on the other hand, has proven benefits.

“Physical activity has been shown to be good for physical and mental health so there’s no reason to believe it wouldn’t be good for 2-and-a-half-year olds,” Dr. Cross said. “It’s also good for developmental health. You want them to be engaged in imaginative play and be interactive.”

“[Outdoor play] gets them away from screens and gives them an opportunity to experience another environment and work on their motor skills and motor planning,” she added. “Exercise will change, briefly, the way our brains process information.”

Dr. Cross added that a lot of motor skills are involved in daily living skills, such as feeding, dressing, and toileting.

Screen time is increasing

The authors acknowledged that screen time may be underestimated by parents. They also noted that they did not have access to what children were watching on the screens.

“This should have been collected because the effect of high screen time differs depending on the type of program,” the authors wrote.

They added that children born in the 2020s may have been exposed to more screen time than the children reared in the early 2010s in this study.

Dr. Cross said screen use in the 2020s may be higher than estimated here and higher in certain populations globally, so it’s not easy to tell if the intervention in this study would have the same mitigating effect on a real-world population.

However, she said, the effect of outdoor play is always going to be helpful for brain development and there’s no downside.

“Exercise is just as important for little kids as it is for grown-ups,” she said.

The authors reported no relevant financial disclosures. Dr. Cross reported no relevant financial disclosures.

*Dr. Jennifer Cross is the correct name, not Dr. Jennifer Frost. The correction was made on Jan. 27, 2023.

Watching a screen more than an hour a day as a toddler is directly linked with poorer communication and daily living skills at age 4, but outdoor play may lessen some of the effects, new research suggests.

The results point to outdoor play as a potential targeted intervention to counter suboptimal brain development in young children who are watching screens at increasingly younger ages.

The findings were published online in JAMA Pediatrics.

The researchers first investigated whether higher screen time (more than 1 hour a day on a device or watching television) at age 2 years is associated with neurodevelopmental outcomes at age 4.

They found the 885 children in the sample from the Japanese Hamamatsu Birth Cohort Study for Mothers and Children who had more screen time had lower scores on communication and daily living skills than children who watched less than an hour a day.

Scores were based on the Vineland Adaptive Behavior Scale according to parent responses to questions. The children included were born between December 2007 and March 2012 and were followed from 18 months to 4 years.

After finding the connection between screen time and lower scores, the researchers investigated whether outdoor play (at least 30 minutes a day) introduced at a 2 years and 8 months made a difference. They considered 6 or 7 days per week frequent outdoor play.
 

Outdoor play mitigated poorer daily living scores

The researchers found that the outdoor play intervention mitigated 18% of the association between high screen time and lower daily living scores but did not mitigate the lower communication scores.

They also found that more screen time at age 2 was significantly linked with infrequent outdoor play at age 32 months (odds ratio, 2.03; 95% confidence interval, 1.48-2.76).

The associations were consistent after taking into account factors including a child’s sex, parental education, and any autism spectrum disorder symptoms at age 18 months.

The authors noted that neurodevelopment concerns with screen use are particularly troubling as the age for use is getting younger.

A recent meta-analysis found that 75% of children younger than 2 use or watch screens, even though guidelines recommend against any screen time before 2.

In addition, the “COVID-19 pandemic led to children having more screen time, less outdoor play, and less physical activity, putting them at potentially greater risk for neurodevelopmental problems,” the authors noted.

“What is concerning is that data show screen time has not decreased after seclusion measures were lifted,” they added.
 

Proven benefits for outdoor play

Jennifer Cross, MD,* assistant professor and section chief for developmental pediatrics at Weill Cornell Medicine, New York, who was not part of the study, said the mitigation properties of outdoor play were something she hadn’t seen before but the concept makes sense.

“The overwhelming evidence is that screen time is not helpful for young children under the age of 2,” she said.

Outdoor play, on the other hand, has proven benefits.

“Physical activity has been shown to be good for physical and mental health so there’s no reason to believe it wouldn’t be good for 2-and-a-half-year olds,” Dr. Cross said. “It’s also good for developmental health. You want them to be engaged in imaginative play and be interactive.”

“[Outdoor play] gets them away from screens and gives them an opportunity to experience another environment and work on their motor skills and motor planning,” she added. “Exercise will change, briefly, the way our brains process information.”

Dr. Cross added that a lot of motor skills are involved in daily living skills, such as feeding, dressing, and toileting.

Screen time is increasing

The authors acknowledged that screen time may be underestimated by parents. They also noted that they did not have access to what children were watching on the screens.

“This should have been collected because the effect of high screen time differs depending on the type of program,” the authors wrote.

They added that children born in the 2020s may have been exposed to more screen time than the children reared in the early 2010s in this study.

Dr. Cross said screen use in the 2020s may be higher than estimated here and higher in certain populations globally, so it’s not easy to tell if the intervention in this study would have the same mitigating effect on a real-world population.

However, she said, the effect of outdoor play is always going to be helpful for brain development and there’s no downside.

“Exercise is just as important for little kids as it is for grown-ups,” she said.

The authors reported no relevant financial disclosures. Dr. Cross reported no relevant financial disclosures.

*Dr. Jennifer Cross is the correct name, not Dr. Jennifer Frost. The correction was made on Jan. 27, 2023.

Children with chronically elevated externalizing symptoms, such as behavioral problems, or internalizing symptoms, such as mental health concerns, have an increased risk for poor economic and social outcomes in adulthood, data from a new study suggest.

Children with comorbid externalizing and internalizing symptoms were especially vulnerable to long-term economic and social exclusion.

“Research has mostly studied the outcomes of children with either behavioral problems or depression-anxiety problems. However, comorbidity is the rule rather than the exception in clinical practice,” senior author Massimilliano Orri, PhD, an assistant professor of psychiatry at McGill University and clinical psychologist with the Douglas Mental Health University Institute, both in Montreal, said in an interview.

“Our findings are important, as they show that comorbidity between externalizing and internalizing problems is associated with real-life outcomes that profoundly influence a youth’s chances to participate in society later in life,” he said.

The study was published in JAMA Network Open.
 

Analyzing associations

Dr. Orri and colleagues analyzed data for 3,017 children in the Quebec Longitudinal Study of Kindergarten Children, a population-based birth cohort that enrolled participants in 1986-1987 and 1987-1988 while they were attending kindergarten. The sample included 2,000 children selected at random and 1,017 children who scored at or above the 80th percentile for disruptive behavior problems.

The research team looked at the association between childhood behavioral profiles and economic and social outcomes for ages 19-37 years, including employment earnings, receipt of welfare, intimate partnerships, and having children living in the household. They obtained the outcome data from participants’ tax returns for 1998-2017.

During enrollment in the study, the children’s teachers assessed behavioral symptoms annually for ages 6-12 years using the Social Behavior Questionnaire. Based on the assessments, the research team categorized the students as having no or low symptoms, high externalizing symptoms only (such as hyperactivity, impulsivity, aggression, and rule violation), high internalizing symptoms only (such as anxiety, depression, worry, and social withdrawal), or comorbid symptoms. They looked at other variables as well, including the child’s sex, the parents’ age at the birth of their first child, the parents’ years of education, family structure, and the parents’ household income.

Among the 3,017 participants, 45.4% of children had no or low symptoms, 29.2% had high externalizing symptoms, 11.7% had high internalizing symptoms, and 13.7% had comorbid symptoms. About 53% were boys, and 47% were girls.

In general, boys were more likely to exhibit high externalizing symptoms, and girls were more likely to exhibit high internalizing symptoms. In the comorbid group, about 82% were boys, and they were more likely to have younger mothers, come from households with lower earnings when they were ages 3-5 years, and have a nonintact family at age 6 years.

The average age at follow-up was 37 years. Participants earned an average of $32,800 per year at ages 33-37 years (between 2013 and 2017). During the 20 years of follow-up, participants received welfare support for about 1.5 years, had an intimate partner for 7.4 years, and had children living in the household for 11 years.

Overall, participants in the high externalizing and high internalizing symptom profiles – and especially those in the comorbid profile – had lower earnings and a higher incidence of annual welfare receipt across early adulthood, compared with participants with low or no symptoms. They were also less likely to have an intimate partner or have children living in the household. Participants with a comorbid symptom profile earned $15,031 less per year and had a 3.79-times higher incidence of annual welfare receipt.
 

Lower earnings

Across the sample, men were more likely to have higher earnings and less likely to receive welfare each year, but they also were less likely to have an intimate partner or have children in the household. Among those with the high externalizing profile, men were significantly less likely to receive welfare. Among the comorbid profile, men were less likely to have children in the household.

Compared with the no-symptom or low-symptom profile, those in the high externalizing profile earned $5,904 less per year and had a two-times–higher incidence of welfare receipt. Those in the high internalizing profile earned $8,473 less per year, had a 2.07-times higher incidence of welfare receipt, and had a lower incidence of intimate partnership.

Compared with the high externalizing profile, those in the comorbid profile earned $9,126 less per year, had a higher incidence of annual welfare receipt, had a lower incidence of intimate partnership, and were less likely to have children in the household. Similarly, compared with the high internalizing profile, those in the comorbid profile earned $6,558 less per year and were more likely to exhibit the other poor long-term outcomes. Participants in the high internalizing profile earned $2,568 less per year than those in the high externalizing profile.

During a 40-year working career, the estimated lost personal employment earnings were $140,515 for the high externalizing profile, $201,657 for the high internalizing profile, and $357,737 for the comorbid profile, compared with those in the no-symptom or low-symptom profile.

“We know that children with externalizing and internalizing symptoms can have many problems in the short term – like social difficulties and lower education attainment – but it’s important to also understand the potential long-term outcomes,” study author Francis Vergunst, DPhil/PhD, an associate professor of child psychosocial difficulties at the University of Oslo, told this news organization.

“For example, when people have insufficient income, are forced to seek welfare support, or lack the social support structure that comes from an intimate partnership, it can have profound consequences for their mental health and well-being – and for society as a whole,” he said. “Understanding this helps to build the case for early prevention programs that can reduce childhood externalizing and internalizing problems and improve long-term outcomes.”

Several mechanisms could explain the associations found across the childhood symptom profiles, the study authors wrote. For instance, children with early behavior problems may be more likely to engage in risky adolescent activities, such as substance use, delinquent peer affiliations, and academic underachievement, which affects their transition to adulthood and accumulation of social and economic capital throughout life. Those with comorbid symptoms likely experience a compounded effect.

Future studies should investigate how to intervene effectively to support children, particularly those with comorbid externalizing and internalizing symptoms, the study authors write.

“Currently, most published studies focus on children with either externalizing or internalizing problems (and these programs can be effective, especially for externalizing problems), but we know very little about how to improve long-term outcomes for children with comorbid symptoms,” Dr. Vergunst said. “Given the large costs of these problems for individuals and society, this is a critical area for further research.”
 

‘Solid evidence’

Commenting on the findings, Ian Colman, PhD, a professor of epidemiology and public health and director of the Applied Psychiatric Epidemiology Across the Life course (APEAL) lab at the University of Ottawa, said, “Research like this provides solid evidence that if we do not provide appropriate supports for children who are struggling with their mental health or related behaviors, then these children are more likely to face a life of social and economic exclusion.”

Dr. Colman, who wasn’t involved with this study, has researched long-term psychosocial outcomes among adolescents with depression, as well as those with externalizing behaviors. He and colleagues have found poorer outcomes among those who exhibit mild or severe difficulties during childhood.

“Studying the long-term outcomes associated with child and adolescent mental and behavioral disorders gives us an idea of how concerned we should be about their future,” he said.

Dr. Vergunst was funded by the Canadian Institute of Health Research and Fonds de Recherche du Quebec Santé postdoctoral fellowships. Dr. Orri and Dr. Colman report no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Children with chronically elevated externalizing symptoms, such as behavioral problems, or internalizing symptoms, such as mental health concerns, have an increased risk for poor economic and social outcomes in adulthood, data from a new study suggest.

Children with comorbid externalizing and internalizing symptoms were especially vulnerable to long-term economic and social exclusion.

“Research has mostly studied the outcomes of children with either behavioral problems or depression-anxiety problems. However, comorbidity is the rule rather than the exception in clinical practice,” senior author Massimilliano Orri, PhD, an assistant professor of psychiatry at McGill University and clinical psychologist with the Douglas Mental Health University Institute, both in Montreal, said in an interview.

“Our findings are important, as they show that comorbidity between externalizing and internalizing problems is associated with real-life outcomes that profoundly influence a youth’s chances to participate in society later in life,” he said.

The study was published in JAMA Network Open.
 

Analyzing associations

Dr. Orri and colleagues analyzed data for 3,017 children in the Quebec Longitudinal Study of Kindergarten Children, a population-based birth cohort that enrolled participants in 1986-1987 and 1987-1988 while they were attending kindergarten. The sample included 2,000 children selected at random and 1,017 children who scored at or above the 80th percentile for disruptive behavior problems.

The research team looked at the association between childhood behavioral profiles and economic and social outcomes for ages 19-37 years, including employment earnings, receipt of welfare, intimate partnerships, and having children living in the household. They obtained the outcome data from participants’ tax returns for 1998-2017.

During enrollment in the study, the children’s teachers assessed behavioral symptoms annually for ages 6-12 years using the Social Behavior Questionnaire. Based on the assessments, the research team categorized the students as having no or low symptoms, high externalizing symptoms only (such as hyperactivity, impulsivity, aggression, and rule violation), high internalizing symptoms only (such as anxiety, depression, worry, and social withdrawal), or comorbid symptoms. They looked at other variables as well, including the child’s sex, the parents’ age at the birth of their first child, the parents’ years of education, family structure, and the parents’ household income.

Among the 3,017 participants, 45.4% of children had no or low symptoms, 29.2% had high externalizing symptoms, 11.7% had high internalizing symptoms, and 13.7% had comorbid symptoms. About 53% were boys, and 47% were girls.

In general, boys were more likely to exhibit high externalizing symptoms, and girls were more likely to exhibit high internalizing symptoms. In the comorbid group, about 82% were boys, and they were more likely to have younger mothers, come from households with lower earnings when they were ages 3-5 years, and have a nonintact family at age 6 years.

The average age at follow-up was 37 years. Participants earned an average of $32,800 per year at ages 33-37 years (between 2013 and 2017). During the 20 years of follow-up, participants received welfare support for about 1.5 years, had an intimate partner for 7.4 years, and had children living in the household for 11 years.

Overall, participants in the high externalizing and high internalizing symptom profiles – and especially those in the comorbid profile – had lower earnings and a higher incidence of annual welfare receipt across early adulthood, compared with participants with low or no symptoms. They were also less likely to have an intimate partner or have children living in the household. Participants with a comorbid symptom profile earned $15,031 less per year and had a 3.79-times higher incidence of annual welfare receipt.
 

Lower earnings

Across the sample, men were more likely to have higher earnings and less likely to receive welfare each year, but they also were less likely to have an intimate partner or have children in the household. Among those with the high externalizing profile, men were significantly less likely to receive welfare. Among the comorbid profile, men were less likely to have children in the household.

Compared with the no-symptom or low-symptom profile, those in the high externalizing profile earned $5,904 less per year and had a two-times–higher incidence of welfare receipt. Those in the high internalizing profile earned $8,473 less per year, had a 2.07-times higher incidence of welfare receipt, and had a lower incidence of intimate partnership.

Compared with the high externalizing profile, those in the comorbid profile earned $9,126 less per year, had a higher incidence of annual welfare receipt, had a lower incidence of intimate partnership, and were less likely to have children in the household. Similarly, compared with the high internalizing profile, those in the comorbid profile earned $6,558 less per year and were more likely to exhibit the other poor long-term outcomes. Participants in the high internalizing profile earned $2,568 less per year than those in the high externalizing profile.

During a 40-year working career, the estimated lost personal employment earnings were $140,515 for the high externalizing profile, $201,657 for the high internalizing profile, and $357,737 for the comorbid profile, compared with those in the no-symptom or low-symptom profile.

“We know that children with externalizing and internalizing symptoms can have many problems in the short term – like social difficulties and lower education attainment – but it’s important to also understand the potential long-term outcomes,” study author Francis Vergunst, DPhil/PhD, an associate professor of child psychosocial difficulties at the University of Oslo, told this news organization.

“For example, when people have insufficient income, are forced to seek welfare support, or lack the social support structure that comes from an intimate partnership, it can have profound consequences for their mental health and well-being – and for society as a whole,” he said. “Understanding this helps to build the case for early prevention programs that can reduce childhood externalizing and internalizing problems and improve long-term outcomes.”

Several mechanisms could explain the associations found across the childhood symptom profiles, the study authors wrote. For instance, children with early behavior problems may be more likely to engage in risky adolescent activities, such as substance use, delinquent peer affiliations, and academic underachievement, which affects their transition to adulthood and accumulation of social and economic capital throughout life. Those with comorbid symptoms likely experience a compounded effect.

Future studies should investigate how to intervene effectively to support children, particularly those with comorbid externalizing and internalizing symptoms, the study authors write.

“Currently, most published studies focus on children with either externalizing or internalizing problems (and these programs can be effective, especially for externalizing problems), but we know very little about how to improve long-term outcomes for children with comorbid symptoms,” Dr. Vergunst said. “Given the large costs of these problems for individuals and society, this is a critical area for further research.”
 

‘Solid evidence’

Commenting on the findings, Ian Colman, PhD, a professor of epidemiology and public health and director of the Applied Psychiatric Epidemiology Across the Life course (APEAL) lab at the University of Ottawa, said, “Research like this provides solid evidence that if we do not provide appropriate supports for children who are struggling with their mental health or related behaviors, then these children are more likely to face a life of social and economic exclusion.”

Dr. Colman, who wasn’t involved with this study, has researched long-term psychosocial outcomes among adolescents with depression, as well as those with externalizing behaviors. He and colleagues have found poorer outcomes among those who exhibit mild or severe difficulties during childhood.

“Studying the long-term outcomes associated with child and adolescent mental and behavioral disorders gives us an idea of how concerned we should be about their future,” he said.

Dr. Vergunst was funded by the Canadian Institute of Health Research and Fonds de Recherche du Quebec Santé postdoctoral fellowships. Dr. Orri and Dr. Colman report no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Children with chronically elevated externalizing symptoms, such as behavioral problems, or internalizing symptoms, such as mental health concerns, have an increased risk for poor economic and social outcomes in adulthood, data from a new study suggest.

Children with comorbid externalizing and internalizing symptoms were especially vulnerable to long-term economic and social exclusion.

“Research has mostly studied the outcomes of children with either behavioral problems or depression-anxiety problems. However, comorbidity is the rule rather than the exception in clinical practice,” senior author Massimilliano Orri, PhD, an assistant professor of psychiatry at McGill University and clinical psychologist with the Douglas Mental Health University Institute, both in Montreal, said in an interview.

“Our findings are important, as they show that comorbidity between externalizing and internalizing problems is associated with real-life outcomes that profoundly influence a youth’s chances to participate in society later in life,” he said.

The study was published in JAMA Network Open.
 

Analyzing associations

Dr. Orri and colleagues analyzed data for 3,017 children in the Quebec Longitudinal Study of Kindergarten Children, a population-based birth cohort that enrolled participants in 1986-1987 and 1987-1988 while they were attending kindergarten. The sample included 2,000 children selected at random and 1,017 children who scored at or above the 80th percentile for disruptive behavior problems.

The research team looked at the association between childhood behavioral profiles and economic and social outcomes for ages 19-37 years, including employment earnings, receipt of welfare, intimate partnerships, and having children living in the household. They obtained the outcome data from participants’ tax returns for 1998-2017.

During enrollment in the study, the children’s teachers assessed behavioral symptoms annually for ages 6-12 years using the Social Behavior Questionnaire. Based on the assessments, the research team categorized the students as having no or low symptoms, high externalizing symptoms only (such as hyperactivity, impulsivity, aggression, and rule violation), high internalizing symptoms only (such as anxiety, depression, worry, and social withdrawal), or comorbid symptoms. They looked at other variables as well, including the child’s sex, the parents’ age at the birth of their first child, the parents’ years of education, family structure, and the parents’ household income.

Among the 3,017 participants, 45.4% of children had no or low symptoms, 29.2% had high externalizing symptoms, 11.7% had high internalizing symptoms, and 13.7% had comorbid symptoms. About 53% were boys, and 47% were girls.

In general, boys were more likely to exhibit high externalizing symptoms, and girls were more likely to exhibit high internalizing symptoms. In the comorbid group, about 82% were boys, and they were more likely to have younger mothers, come from households with lower earnings when they were ages 3-5 years, and have a nonintact family at age 6 years.

The average age at follow-up was 37 years. Participants earned an average of $32,800 per year at ages 33-37 years (between 2013 and 2017). During the 20 years of follow-up, participants received welfare support for about 1.5 years, had an intimate partner for 7.4 years, and had children living in the household for 11 years.

Overall, participants in the high externalizing and high internalizing symptom profiles – and especially those in the comorbid profile – had lower earnings and a higher incidence of annual welfare receipt across early adulthood, compared with participants with low or no symptoms. They were also less likely to have an intimate partner or have children living in the household. Participants with a comorbid symptom profile earned $15,031 less per year and had a 3.79-times higher incidence of annual welfare receipt.
 

Lower earnings

Across the sample, men were more likely to have higher earnings and less likely to receive welfare each year, but they also were less likely to have an intimate partner or have children in the household. Among those with the high externalizing profile, men were significantly less likely to receive welfare. Among the comorbid profile, men were less likely to have children in the household.

Compared with the no-symptom or low-symptom profile, those in the high externalizing profile earned $5,904 less per year and had a two-times–higher incidence of welfare receipt. Those in the high internalizing profile earned $8,473 less per year, had a 2.07-times higher incidence of welfare receipt, and had a lower incidence of intimate partnership.

Compared with the high externalizing profile, those in the comorbid profile earned $9,126 less per year, had a higher incidence of annual welfare receipt, had a lower incidence of intimate partnership, and were less likely to have children in the household. Similarly, compared with the high internalizing profile, those in the comorbid profile earned $6,558 less per year and were more likely to exhibit the other poor long-term outcomes. Participants in the high internalizing profile earned $2,568 less per year than those in the high externalizing profile.

During a 40-year working career, the estimated lost personal employment earnings were $140,515 for the high externalizing profile, $201,657 for the high internalizing profile, and $357,737 for the comorbid profile, compared with those in the no-symptom or low-symptom profile.

“We know that children with externalizing and internalizing symptoms can have many problems in the short term – like social difficulties and lower education attainment – but it’s important to also understand the potential long-term outcomes,” study author Francis Vergunst, DPhil/PhD, an associate professor of child psychosocial difficulties at the University of Oslo, told this news organization.

“For example, when people have insufficient income, are forced to seek welfare support, or lack the social support structure that comes from an intimate partnership, it can have profound consequences for their mental health and well-being – and for society as a whole,” he said. “Understanding this helps to build the case for early prevention programs that can reduce childhood externalizing and internalizing problems and improve long-term outcomes.”

Several mechanisms could explain the associations found across the childhood symptom profiles, the study authors wrote. For instance, children with early behavior problems may be more likely to engage in risky adolescent activities, such as substance use, delinquent peer affiliations, and academic underachievement, which affects their transition to adulthood and accumulation of social and economic capital throughout life. Those with comorbid symptoms likely experience a compounded effect.

Future studies should investigate how to intervene effectively to support children, particularly those with comorbid externalizing and internalizing symptoms, the study authors write.

“Currently, most published studies focus on children with either externalizing or internalizing problems (and these programs can be effective, especially for externalizing problems), but we know very little about how to improve long-term outcomes for children with comorbid symptoms,” Dr. Vergunst said. “Given the large costs of these problems for individuals and society, this is a critical area for further research.”
 

‘Solid evidence’

Commenting on the findings, Ian Colman, PhD, a professor of epidemiology and public health and director of the Applied Psychiatric Epidemiology Across the Life course (APEAL) lab at the University of Ottawa, said, “Research like this provides solid evidence that if we do not provide appropriate supports for children who are struggling with their mental health or related behaviors, then these children are more likely to face a life of social and economic exclusion.”

Dr. Colman, who wasn’t involved with this study, has researched long-term psychosocial outcomes among adolescents with depression, as well as those with externalizing behaviors. He and colleagues have found poorer outcomes among those who exhibit mild or severe difficulties during childhood.

“Studying the long-term outcomes associated with child and adolescent mental and behavioral disorders gives us an idea of how concerned we should be about their future,” he said.

Dr. Vergunst was funded by the Canadian Institute of Health Research and Fonds de Recherche du Quebec Santé postdoctoral fellowships. Dr. Orri and Dr. Colman report no relevant financial relationships.

A version of this article first appeared on Medscape.com.

FROM WORLD JOURNAL OF GASTROENTEROLOGY

One year after a diagnosis of celiac disease, more than one in five children present with functional gastrointestinal disorders (FGIDs) despite following a gluten-free diet (GFD). Developing FGIDs may be linked to caloric intake and percentage of food fat, but it does not change between a GFD with processed foods or a GFD with natural products.

These are the main findings of a study run jointly by the “Federico II” University of Naples and the “Luigi Vanvitelli” University of Campania, the results of which were published in the World Journal of Gastroenterology.

Unlike in previous studies, the criteria used in this study (the Rome IV criteria) allowed investigators to diagnose FGIDs even when other organic diseases, such as celiac disease or chronic inflammatory bowel disease, were present. The evidence obtained shows that adult individuals with celiac disease are at an increased risk for functional abdominal pain, even if they adhere well to a GFD. The researchers at the University of Campania wanted to determine the prevalence of FGIDs in the pediatric age group, which has been a poorly explored area.

The study authors enrolled 104 pediatric patients (aged 1-18 years) who had been diagnosed with celiac disease. The patients were randomly divided into two groups. Group A (n = 55) received a controlled GFD with processed foods (diet 1), and group B (n = 49) received a controlled GFD with > 60% natural products (diet 2). The presence of FGIDs was assessed at diagnosis (T0) and after 12 months (T1), and any potential link to the type of diet was analyzed.

The number of symptomatic children at enrollment was 30 of 55 (54.5%) in group A and 25 of 49 (51%) in group B. After 12 months, despite negative serology for celiac disease, the prevalence of FGIDs was 10/55 (18%) in group A and 8/49 (16.3%) in group B. There was no statistically significant difference between the two groups at T1. The most common disorder was functional constipation, followed by postprandial distress syndrome. At T1, the macro- and micronutrient intake was similar between the two groups, with no significant differences in nutrient analysis. However, in both groups, the prevalence of FGIDs was lower in patients who were consuming fewer calories (odds ratio [OR], 0.99; 95% confidence interval [CI], 0.99-1.00) and fat (OR, 0.33; 95% CI, 0.65-0.95). The figure was very close to being statistically significant (P = .055).

“This is the first study to show that the presence of functional GI symptoms in children with celiac disease on a GFD are possibly related to higher caloric and fat intake,” wrote the study authors. “It remains to be determined whether the risk is due to the persistence of a chronic inflammatory process or to nutritional factors. Long-term monitoring studies will assist in determining the natural history of these functional symptoms.”

The study authors reported having no relevant financial conflicts.

This article was translated from Univadis Italy and a version appeared on Medscape.com.

FROM WORLD JOURNAL OF GASTROENTEROLOGY

One year after a diagnosis of celiac disease, more than one in five children present with functional gastrointestinal disorders (FGIDs) despite following a gluten-free diet (GFD). Developing FGIDs may be linked to caloric intake and percentage of food fat, but it does not change between a GFD with processed foods or a GFD with natural products.

These are the main findings of a study run jointly by the “Federico II” University of Naples and the “Luigi Vanvitelli” University of Campania, the results of which were published in the World Journal of Gastroenterology.

Unlike in previous studies, the criteria used in this study (the Rome IV criteria) allowed investigators to diagnose FGIDs even when other organic diseases, such as celiac disease or chronic inflammatory bowel disease, were present. The evidence obtained shows that adult individuals with celiac disease are at an increased risk for functional abdominal pain, even if they adhere well to a GFD. The researchers at the University of Campania wanted to determine the prevalence of FGIDs in the pediatric age group, which has been a poorly explored area.

The study authors enrolled 104 pediatric patients (aged 1-18 years) who had been diagnosed with celiac disease. The patients were randomly divided into two groups. Group A (n = 55) received a controlled GFD with processed foods (diet 1), and group B (n = 49) received a controlled GFD with > 60% natural products (diet 2). The presence of FGIDs was assessed at diagnosis (T0) and after 12 months (T1), and any potential link to the type of diet was analyzed.

The number of symptomatic children at enrollment was 30 of 55 (54.5%) in group A and 25 of 49 (51%) in group B. After 12 months, despite negative serology for celiac disease, the prevalence of FGIDs was 10/55 (18%) in group A and 8/49 (16.3%) in group B. There was no statistically significant difference between the two groups at T1. The most common disorder was functional constipation, followed by postprandial distress syndrome. At T1, the macro- and micronutrient intake was similar between the two groups, with no significant differences in nutrient analysis. However, in both groups, the prevalence of FGIDs was lower in patients who were consuming fewer calories (odds ratio [OR], 0.99; 95% confidence interval [CI], 0.99-1.00) and fat (OR, 0.33; 95% CI, 0.65-0.95). The figure was very close to being statistically significant (P = .055).

“This is the first study to show that the presence of functional GI symptoms in children with celiac disease on a GFD are possibly related to higher caloric and fat intake,” wrote the study authors. “It remains to be determined whether the risk is due to the persistence of a chronic inflammatory process or to nutritional factors. Long-term monitoring studies will assist in determining the natural history of these functional symptoms.”

The study authors reported having no relevant financial conflicts.

This article was translated from Univadis Italy and a version appeared on Medscape.com.

FROM WORLD JOURNAL OF GASTROENTEROLOGY

One year after a diagnosis of celiac disease, more than one in five children present with functional gastrointestinal disorders (FGIDs) despite following a gluten-free diet (GFD). Developing FGIDs may be linked to caloric intake and percentage of food fat, but it does not change between a GFD with processed foods or a GFD with natural products.

These are the main findings of a study run jointly by the “Federico II” University of Naples and the “Luigi Vanvitelli” University of Campania, the results of which were published in the World Journal of Gastroenterology.

Unlike in previous studies, the criteria used in this study (the Rome IV criteria) allowed investigators to diagnose FGIDs even when other organic diseases, such as celiac disease or chronic inflammatory bowel disease, were present. The evidence obtained shows that adult individuals with celiac disease are at an increased risk for functional abdominal pain, even if they adhere well to a GFD. The researchers at the University of Campania wanted to determine the prevalence of FGIDs in the pediatric age group, which has been a poorly explored area.

The study authors enrolled 104 pediatric patients (aged 1-18 years) who had been diagnosed with celiac disease. The patients were randomly divided into two groups. Group A (n = 55) received a controlled GFD with processed foods (diet 1), and group B (n = 49) received a controlled GFD with > 60% natural products (diet 2). The presence of FGIDs was assessed at diagnosis (T0) and after 12 months (T1), and any potential link to the type of diet was analyzed.

The number of symptomatic children at enrollment was 30 of 55 (54.5%) in group A and 25 of 49 (51%) in group B. After 12 months, despite negative serology for celiac disease, the prevalence of FGIDs was 10/55 (18%) in group A and 8/49 (16.3%) in group B. There was no statistically significant difference between the two groups at T1. The most common disorder was functional constipation, followed by postprandial distress syndrome. At T1, the macro- and micronutrient intake was similar between the two groups, with no significant differences in nutrient analysis. However, in both groups, the prevalence of FGIDs was lower in patients who were consuming fewer calories (odds ratio [OR], 0.99; 95% confidence interval [CI], 0.99-1.00) and fat (OR, 0.33; 95% CI, 0.65-0.95). The figure was very close to being statistically significant (P = .055).

“This is the first study to show that the presence of functional GI symptoms in children with celiac disease on a GFD are possibly related to higher caloric and fat intake,” wrote the study authors. “It remains to be determined whether the risk is due to the persistence of a chronic inflammatory process or to nutritional factors. Long-term monitoring studies will assist in determining the natural history of these functional symptoms.”

The study authors reported having no relevant financial conflicts.

This article was translated from Univadis Italy and a version appeared on Medscape.com.

A new prognostic tool may help identify infants with cerebral palsy (CP) earlier, allowing them to receive therapies to improve later outcomes.
 

Researchers from Canada used 12 clinical variables to predict the condition. The tool accurately predicted 75% of CP cases. The study was published in JAMA Pediatrics.

The prevalence of CP in the United States is 2-3 children per 1,000, a rate that has been relatively unchanged for decades. Although recent innovations in diagnosis using motor scores and MRI scans have aided in diagnosis, these techniques have historically been reserved only for infants who were cared for in neonatal intensive care units, were born prematurely, or who had other neurologic risk factors, such as birth defects.

The tool identified 2.4 times more children with CP than would have been detected using current diagnostic methods, according to the researchers.

“We developed the prediction tool to try to make these findings accessible to any health care provider, which will hopefully help break down the long-held perception that CP is usually related to prematurity or a difficult delivery,” said Mary Dunbar, MD, an author of the study. “We know that about half of children with CP aren’t premature and didn’t have a particularly difficult birth.”

The bedside tool weighs factors such as the use by mothers of illicit drugs and tobacco; the presence of diabetes and preeclampsia during pregnancy; whether the infant is male; birth weight; and the number of miscarriages the mother had prior to the birth. The tool also factors in results from a test that measures how well the infant is adjusting to life outside the womb.

Dr. Dunbar and colleagues compared 1,265 infants with CP from the Canadian Cerebral Palsy Registry from 2003 to 2019 with a control group of 1,985 children without CP from the Alberta Pregnancy Outcomes and Nutrition longitudinal study.

The study authors hope that the prognostic tool can be integrated into existing newborn screenings and completed by nurses or physicians as part of routine care.

“Its cost is low especially in comparison to MRI and specialized neurological assessments,” said Sarah Taylor, MD, section chief of neonatal-perinatal medicine at Yale New Haven Children’s Hospital in New Haven, Conn. Health systems and doctors may be more apt to adopt the tool, since it does not require specialized equipment or training.
 

Surprising findings

Several clinical variables independently increased the risk of CP, including independent 5-minute Apgar test scores of <6, chorioamnionitis, and illicit drug use during the pregnancy. Dr. Dunbar and colleagues recommend that primary care clinicians provide enhanced surveillance for these infants.

“I think there are also really important public health implications to address maternal and reproductive health to support pregnant people, since this study shows that common pregnancy conditions that are potentially treatable may additively contribute to cerebral palsy risk,” said Dr. Dunbar, a pediatric neurologist and assistant professor at the University of Calgary (Alta.)

For infants identified as being at risk, the study authors also suggest that doctors conduct focused examinations for CP at 3-, 6- and 12-month well-baby visits. If results of an examination are abnormal, doctors can advise the caregiver to conduct an early expert evaluation for a general movements assessment. Interventions for children with CP usually start in the first few years of life and can include occupational therapy, use of orthotic devices, and medication.

Dr. Dunbar and colleagues acknowledge that the test is not perfect and that additional work is needed.

“As helpful as the prediction tool may be to identify cases of CP early, we know there are still a minority of CP cases that it won’t catch because they don’t have any of the known risk factors,” Dr. Dunbar said. “We’re currently working on further research about this unique group.”

The researchers cited several limitations to the dataset used in the study, including a control group that was skewed toward older patients and persons of higher socioeconomic status. In addition, the data included a greater proportion of White women than the average Canadian population.

The Canadian Cerebral Palsy Registry was supported by the NeuroDevNet, KidsBrainHealth, the Harvey Guyda Chair of McGill University, Montreal Children’s Hospital, and the Public Health Agency of Canada. The authors disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

A new prognostic tool may help identify infants with cerebral palsy (CP) earlier, allowing them to receive therapies to improve later outcomes.
 

Researchers from Canada used 12 clinical variables to predict the condition. The tool accurately predicted 75% of CP cases. The study was published in JAMA Pediatrics.

The prevalence of CP in the United States is 2-3 children per 1,000, a rate that has been relatively unchanged for decades. Although recent innovations in diagnosis using motor scores and MRI scans have aided in diagnosis, these techniques have historically been reserved only for infants who were cared for in neonatal intensive care units, were born prematurely, or who had other neurologic risk factors, such as birth defects.

The tool identified 2.4 times more children with CP than would have been detected using current diagnostic methods, according to the researchers.

“We developed the prediction tool to try to make these findings accessible to any health care provider, which will hopefully help break down the long-held perception that CP is usually related to prematurity or a difficult delivery,” said Mary Dunbar, MD, an author of the study. “We know that about half of children with CP aren’t premature and didn’t have a particularly difficult birth.”

The bedside tool weighs factors such as the use by mothers of illicit drugs and tobacco; the presence of diabetes and preeclampsia during pregnancy; whether the infant is male; birth weight; and the number of miscarriages the mother had prior to the birth. The tool also factors in results from a test that measures how well the infant is adjusting to life outside the womb.

Dr. Dunbar and colleagues compared 1,265 infants with CP from the Canadian Cerebral Palsy Registry from 2003 to 2019 with a control group of 1,985 children without CP from the Alberta Pregnancy Outcomes and Nutrition longitudinal study.

The study authors hope that the prognostic tool can be integrated into existing newborn screenings and completed by nurses or physicians as part of routine care.

“Its cost is low especially in comparison to MRI and specialized neurological assessments,” said Sarah Taylor, MD, section chief of neonatal-perinatal medicine at Yale New Haven Children’s Hospital in New Haven, Conn. Health systems and doctors may be more apt to adopt the tool, since it does not require specialized equipment or training.
 

Surprising findings

Several clinical variables independently increased the risk of CP, including independent 5-minute Apgar test scores of <6, chorioamnionitis, and illicit drug use during the pregnancy. Dr. Dunbar and colleagues recommend that primary care clinicians provide enhanced surveillance for these infants.

“I think there are also really important public health implications to address maternal and reproductive health to support pregnant people, since this study shows that common pregnancy conditions that are potentially treatable may additively contribute to cerebral palsy risk,” said Dr. Dunbar, a pediatric neurologist and assistant professor at the University of Calgary (Alta.)

For infants identified as being at risk, the study authors also suggest that doctors conduct focused examinations for CP at 3-, 6- and 12-month well-baby visits. If results of an examination are abnormal, doctors can advise the caregiver to conduct an early expert evaluation for a general movements assessment. Interventions for children with CP usually start in the first few years of life and can include occupational therapy, use of orthotic devices, and medication.

Dr. Dunbar and colleagues acknowledge that the test is not perfect and that additional work is needed.

“As helpful as the prediction tool may be to identify cases of CP early, we know there are still a minority of CP cases that it won’t catch because they don’t have any of the known risk factors,” Dr. Dunbar said. “We’re currently working on further research about this unique group.”

The researchers cited several limitations to the dataset used in the study, including a control group that was skewed toward older patients and persons of higher socioeconomic status. In addition, the data included a greater proportion of White women than the average Canadian population.

The Canadian Cerebral Palsy Registry was supported by the NeuroDevNet, KidsBrainHealth, the Harvey Guyda Chair of McGill University, Montreal Children’s Hospital, and the Public Health Agency of Canada. The authors disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

A new prognostic tool may help identify infants with cerebral palsy (CP) earlier, allowing them to receive therapies to improve later outcomes.
 

Researchers from Canada used 12 clinical variables to predict the condition. The tool accurately predicted 75% of CP cases. The study was published in JAMA Pediatrics.

The prevalence of CP in the United States is 2-3 children per 1,000, a rate that has been relatively unchanged for decades. Although recent innovations in diagnosis using motor scores and MRI scans have aided in diagnosis, these techniques have historically been reserved only for infants who were cared for in neonatal intensive care units, were born prematurely, or who had other neurologic risk factors, such as birth defects.

The tool identified 2.4 times more children with CP than would have been detected using current diagnostic methods, according to the researchers.

“We developed the prediction tool to try to make these findings accessible to any health care provider, which will hopefully help break down the long-held perception that CP is usually related to prematurity or a difficult delivery,” said Mary Dunbar, MD, an author of the study. “We know that about half of children with CP aren’t premature and didn’t have a particularly difficult birth.”

The bedside tool weighs factors such as the use by mothers of illicit drugs and tobacco; the presence of diabetes and preeclampsia during pregnancy; whether the infant is male; birth weight; and the number of miscarriages the mother had prior to the birth. The tool also factors in results from a test that measures how well the infant is adjusting to life outside the womb.

Dr. Dunbar and colleagues compared 1,265 infants with CP from the Canadian Cerebral Palsy Registry from 2003 to 2019 with a control group of 1,985 children without CP from the Alberta Pregnancy Outcomes and Nutrition longitudinal study.

The study authors hope that the prognostic tool can be integrated into existing newborn screenings and completed by nurses or physicians as part of routine care.

“Its cost is low especially in comparison to MRI and specialized neurological assessments,” said Sarah Taylor, MD, section chief of neonatal-perinatal medicine at Yale New Haven Children’s Hospital in New Haven, Conn. Health systems and doctors may be more apt to adopt the tool, since it does not require specialized equipment or training.
 

Surprising findings

Several clinical variables independently increased the risk of CP, including independent 5-minute Apgar test scores of <6, chorioamnionitis, and illicit drug use during the pregnancy. Dr. Dunbar and colleagues recommend that primary care clinicians provide enhanced surveillance for these infants.

“I think there are also really important public health implications to address maternal and reproductive health to support pregnant people, since this study shows that common pregnancy conditions that are potentially treatable may additively contribute to cerebral palsy risk,” said Dr. Dunbar, a pediatric neurologist and assistant professor at the University of Calgary (Alta.)

For infants identified as being at risk, the study authors also suggest that doctors conduct focused examinations for CP at 3-, 6- and 12-month well-baby visits. If results of an examination are abnormal, doctors can advise the caregiver to conduct an early expert evaluation for a general movements assessment. Interventions for children with CP usually start in the first few years of life and can include occupational therapy, use of orthotic devices, and medication.

Dr. Dunbar and colleagues acknowledge that the test is not perfect and that additional work is needed.

“As helpful as the prediction tool may be to identify cases of CP early, we know there are still a minority of CP cases that it won’t catch because they don’t have any of the known risk factors,” Dr. Dunbar said. “We’re currently working on further research about this unique group.”

The researchers cited several limitations to the dataset used in the study, including a control group that was skewed toward older patients and persons of higher socioeconomic status. In addition, the data included a greater proportion of White women than the average Canadian population.

The Canadian Cerebral Palsy Registry was supported by the NeuroDevNet, KidsBrainHealth, the Harvey Guyda Chair of McGill University, Montreal Children’s Hospital, and the Public Health Agency of Canada. The authors disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

There has been a substantial increase over the last 20 years in antipsychotic prescribing among children and adolescents in England – especially among those with autism, an analysis of primary care records from 7.2 million children and adolescents aged 3-18 years shows.

“This study demonstrates a concerning trend in antipsychotic prescribing in children and adolescents,” study investigator Matthias Pierce, PhD, senior research fellow at the University of Manchester (England) Center for Women’s Mental Health, who jointly led the study, said in a news release.

“We do not think the changes in prescribing necessarily relate to changes in clinical need; rather, it may be more likely to reflect changes in prescribing practice by clinicians,” Dr. Pierce said.

The study was published online in The Lancet Psychiatry.
 

Increase in long-term use

Between 2000 and 2019, prescriptions for antipsychotics nearly doubled from 0.06% to 0.11%.

The investigators note that the U.K.’s National Institute for Health and Care Excellence has approved the use of some antipsychotics in patients younger than age 18 with schizophrenia, bipolar disorder, and severely aggressive behavior attributable to conduct disorder.

However, these data suggest antipsychotics are being prescribed for an increasingly broad range of conditions, most commonly autism, but also for attention-deficit/ hyperactivity disorder, tic disorders like Tourrette syndrome, and learning difficulties.

“Broadening use of antipsychotics in developing young people begs questions about their safety over time and demands more research on this topic,” senior author Kathryn Abel, MBBS, PhD, from the University of Manchester said in the news release.

During the study period, antipsychotic prescribing in primary care increased by an average of 3.3% per year and the rate of first prescriptions increased by 2.2% per year.

The data also suggest that more children and adolescents are taking these powerful drugs for longer periods of time. The proportion receiving antipsychotics for at least 6 months after an initial prescription rose from 41.9% in 2000 to 62.8% in 2018.
 

Prescribing inequities

From 2009 onwards, more than 90% of prescriptions were for atypical antipsychotics.

Over time, risperidone dominated, with more than 60% of all prescriptions, followed by aripiprazole, quetiapine, olanzapine, and haloperidol as the most prescribed antipsychotics.

Boys and older children aged 15-18 years were most likely to receive an antipsychotic. However, the increasing trends were evident in all groups.

The data also point to inequities in prescribing as a result of deprivation levels, with typical antipsychotics prescribed more frequently in more deprived areas over time.

Dr. Pierce said he hopes this study will “help clinicians to evaluate the prescribing of antipsychotics to children more fully and will encourage them to consider better access to alternatives.”

Dr. Abel noted that antipsychotic medications “continue to have a valuable role in the treatment of serious mental illness. These findings represent a descriptive account of antipsychotic prescribing to children and adolescents in the U.K. today and provide a window onto current practice.”
 

Findings are no surprise

Emily Simonoff, MD, professor of child and adolescent psychiatry, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, offered perspective on the study in a statement from the U.K. nonprofit Science Media Centre.

“To clinicians, it will not be surprising that the authors demonstrate an increase in rates of prescriptions over that time period, as there has been a steadily emerging evidence base for the benefits of this group of medication for a range of different indications, which has been further supported by new licensing indications and recommendations from NICE,” Dr. Simonoff said.

For example, “there is good evidence for their benefits for other conditions such as irritability in autism spectrum disorder.

“However, it should also be noted that NICE recommendations for their use in many conditions is as part of a multimodal treatment plan, for example including psychological or behavioral interventions. It’s unclear from the study whether such recommendations were being followed or medication was being used on its own,” she added.

Dr. Simonoff also said it’s “reassuring” that prescribing rates remain very low in the youngest children and notes that the authors “rightly highlight the need for high-quality, longer-term studies on efficacy and, most importantly, adverse effects. This should be a research priority.”

The study had no funding. The authors report no relevant financial relationships. Dr. Simonoff is a member of the NICE guideline development group for the management of autism and has published on the efficacy of antipsychotic medication for irritability in autism.

A version of this article first appeared on Medscape.com.

There has been a substantial increase over the last 20 years in antipsychotic prescribing among children and adolescents in England – especially among those with autism, an analysis of primary care records from 7.2 million children and adolescents aged 3-18 years shows.

“This study demonstrates a concerning trend in antipsychotic prescribing in children and adolescents,” study investigator Matthias Pierce, PhD, senior research fellow at the University of Manchester (England) Center for Women’s Mental Health, who jointly led the study, said in a news release.

“We do not think the changes in prescribing necessarily relate to changes in clinical need; rather, it may be more likely to reflect changes in prescribing practice by clinicians,” Dr. Pierce said.

The study was published online in The Lancet Psychiatry.
 

Increase in long-term use

Between 2000 and 2019, prescriptions for antipsychotics nearly doubled from 0.06% to 0.11%.

The investigators note that the U.K.’s National Institute for Health and Care Excellence has approved the use of some antipsychotics in patients younger than age 18 with schizophrenia, bipolar disorder, and severely aggressive behavior attributable to conduct disorder.

However, these data suggest antipsychotics are being prescribed for an increasingly broad range of conditions, most commonly autism, but also for attention-deficit/ hyperactivity disorder, tic disorders like Tourrette syndrome, and learning difficulties.

“Broadening use of antipsychotics in developing young people begs questions about their safety over time and demands more research on this topic,” senior author Kathryn Abel, MBBS, PhD, from the University of Manchester said in the news release.

During the study period, antipsychotic prescribing in primary care increased by an average of 3.3% per year and the rate of first prescriptions increased by 2.2% per year.

The data also suggest that more children and adolescents are taking these powerful drugs for longer periods of time. The proportion receiving antipsychotics for at least 6 months after an initial prescription rose from 41.9% in 2000 to 62.8% in 2018.
 

Prescribing inequities

From 2009 onwards, more than 90% of prescriptions were for atypical antipsychotics.

Over time, risperidone dominated, with more than 60% of all prescriptions, followed by aripiprazole, quetiapine, olanzapine, and haloperidol as the most prescribed antipsychotics.

Boys and older children aged 15-18 years were most likely to receive an antipsychotic. However, the increasing trends were evident in all groups.

The data also point to inequities in prescribing as a result of deprivation levels, with typical antipsychotics prescribed more frequently in more deprived areas over time.

Dr. Pierce said he hopes this study will “help clinicians to evaluate the prescribing of antipsychotics to children more fully and will encourage them to consider better access to alternatives.”

Dr. Abel noted that antipsychotic medications “continue to have a valuable role in the treatment of serious mental illness. These findings represent a descriptive account of antipsychotic prescribing to children and adolescents in the U.K. today and provide a window onto current practice.”
 

Findings are no surprise

Emily Simonoff, MD, professor of child and adolescent psychiatry, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, offered perspective on the study in a statement from the U.K. nonprofit Science Media Centre.

“To clinicians, it will not be surprising that the authors demonstrate an increase in rates of prescriptions over that time period, as there has been a steadily emerging evidence base for the benefits of this group of medication for a range of different indications, which has been further supported by new licensing indications and recommendations from NICE,” Dr. Simonoff said.

For example, “there is good evidence for their benefits for other conditions such as irritability in autism spectrum disorder.

“However, it should also be noted that NICE recommendations for their use in many conditions is as part of a multimodal treatment plan, for example including psychological or behavioral interventions. It’s unclear from the study whether such recommendations were being followed or medication was being used on its own,” she added.

Dr. Simonoff also said it’s “reassuring” that prescribing rates remain very low in the youngest children and notes that the authors “rightly highlight the need for high-quality, longer-term studies on efficacy and, most importantly, adverse effects. This should be a research priority.”

The study had no funding. The authors report no relevant financial relationships. Dr. Simonoff is a member of the NICE guideline development group for the management of autism and has published on the efficacy of antipsychotic medication for irritability in autism.

A version of this article first appeared on Medscape.com.

There has been a substantial increase over the last 20 years in antipsychotic prescribing among children and adolescents in England – especially among those with autism, an analysis of primary care records from 7.2 million children and adolescents aged 3-18 years shows.

“This study demonstrates a concerning trend in antipsychotic prescribing in children and adolescents,” study investigator Matthias Pierce, PhD, senior research fellow at the University of Manchester (England) Center for Women’s Mental Health, who jointly led the study, said in a news release.

“We do not think the changes in prescribing necessarily relate to changes in clinical need; rather, it may be more likely to reflect changes in prescribing practice by clinicians,” Dr. Pierce said.

The study was published online in The Lancet Psychiatry.
 

Increase in long-term use

Between 2000 and 2019, prescriptions for antipsychotics nearly doubled from 0.06% to 0.11%.

The investigators note that the U.K.’s National Institute for Health and Care Excellence has approved the use of some antipsychotics in patients younger than age 18 with schizophrenia, bipolar disorder, and severely aggressive behavior attributable to conduct disorder.

However, these data suggest antipsychotics are being prescribed for an increasingly broad range of conditions, most commonly autism, but also for attention-deficit/ hyperactivity disorder, tic disorders like Tourrette syndrome, and learning difficulties.

“Broadening use of antipsychotics in developing young people begs questions about their safety over time and demands more research on this topic,” senior author Kathryn Abel, MBBS, PhD, from the University of Manchester said in the news release.

During the study period, antipsychotic prescribing in primary care increased by an average of 3.3% per year and the rate of first prescriptions increased by 2.2% per year.

The data also suggest that more children and adolescents are taking these powerful drugs for longer periods of time. The proportion receiving antipsychotics for at least 6 months after an initial prescription rose from 41.9% in 2000 to 62.8% in 2018.
 

Prescribing inequities

From 2009 onwards, more than 90% of prescriptions were for atypical antipsychotics.

Over time, risperidone dominated, with more than 60% of all prescriptions, followed by aripiprazole, quetiapine, olanzapine, and haloperidol as the most prescribed antipsychotics.

Boys and older children aged 15-18 years were most likely to receive an antipsychotic. However, the increasing trends were evident in all groups.

The data also point to inequities in prescribing as a result of deprivation levels, with typical antipsychotics prescribed more frequently in more deprived areas over time.

Dr. Pierce said he hopes this study will “help clinicians to evaluate the prescribing of antipsychotics to children more fully and will encourage them to consider better access to alternatives.”

Dr. Abel noted that antipsychotic medications “continue to have a valuable role in the treatment of serious mental illness. These findings represent a descriptive account of antipsychotic prescribing to children and adolescents in the U.K. today and provide a window onto current practice.”
 

Findings are no surprise

Emily Simonoff, MD, professor of child and adolescent psychiatry, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, offered perspective on the study in a statement from the U.K. nonprofit Science Media Centre.

“To clinicians, it will not be surprising that the authors demonstrate an increase in rates of prescriptions over that time period, as there has been a steadily emerging evidence base for the benefits of this group of medication for a range of different indications, which has been further supported by new licensing indications and recommendations from NICE,” Dr. Simonoff said.

For example, “there is good evidence for their benefits for other conditions such as irritability in autism spectrum disorder.

“However, it should also be noted that NICE recommendations for their use in many conditions is as part of a multimodal treatment plan, for example including psychological or behavioral interventions. It’s unclear from the study whether such recommendations were being followed or medication was being used on its own,” she added.

Dr. Simonoff also said it’s “reassuring” that prescribing rates remain very low in the youngest children and notes that the authors “rightly highlight the need for high-quality, longer-term studies on efficacy and, most importantly, adverse effects. This should be a research priority.”

The study had no funding. The authors report no relevant financial relationships. Dr. Simonoff is a member of the NICE guideline development group for the management of autism and has published on the efficacy of antipsychotic medication for irritability in autism.

A version of this article first appeared on Medscape.com.

Children and teens with concussions who returned to school sooner showed fewer symptoms after 2 weeks than those who returned to school later, based on data from more than 1,600 individuals aged 5-18 years.

The timing for return to school after a concussion has been the subject of guidelines, but data on how the timing of school returns affects later symptom burdens are limited, Christopher G. Vaughan, PhD, of Children’s National Hospital, Rockville, Md., and colleagues wrote.

Examining how the timing of return to school (RTS) affects later symptoms is needed to inform early postinjury management, they said.

In the new study published in JAMA Network Open, the researchers identified 1,630 children and teens aged 5-18 years who were treated for concussions at nine Canadian pediatric EDs. The primary outcome was symptom burden at 14 days post concussion, based on the Post-Concussion Symptom Inventory (PCSI). Early RTS was defined as missing fewer than 3 days of school post concussion.

Overall, the mean number of missed school days was 3.74 (excluding weekends). When divided by age, the mean number of missed days was 2.61 for children aged 5-7 years, 3.26 for those aged 8-12 years, and 4.71 for those aged 13-18 years.

Slightly more than half (53.7%) of the participants had an early RTS of 2 missed days or fewer. Later RTS was most common in the oldest age group, followed by the middle and younger age groups.

The researchers used a propensity score–matched analysis to determine associations. At 14 days, an early RTS was associated with reduced symptoms among 8- to 12-year-olds and 13- to 18-year-olds, though not in the youngest patients aged 5-7 years. In addition, the researchers created quantiles based on initial symptom ratings.

For the youngest age group, the association between early RTS and reduced symptoms at day 14 was higher among those with lower initial symptoms.

For the two older groups, the association was higher for those with higher initial symptoms (based on the PCSI).

The findings that earlier RTS was associated with a lower symptom burden at day 14 for those with higher levels of symptoms at baseline was surprising, but the mechanisms of the timing and effect of RTS requires more study, the researchers wrote in their discussion.

The effect of early RTS on symptoms may be in part related to factors such as “the benefits of socialization, reduced stress from not missing too much school, maintaining or returning to a normal sleep-wake schedule, and returning to light to moderate physical activity (gym class and recreational activities),” the researchers noted.

Another study related to recovery and concussion recently appeared in Neurology. In that study, the authors found that those athletes who took a longer time to recover from a sports-related concussion could still return to play with additional time off, but the methods and populations differed from the current study, which focused on RTS rather than returning to play.

The current study findings were limited by several factors including the lack of randomization for RTS timing and a lack of data on the variety of potential supports and accommodations students received, the researchers noted.

However, the results were strengthened by the large size and diverse nature of the concussions, and the roughly equal representation of boys and girls, they said.

Although randomized trials are needed to determine the best timing for RTS, the current study suggests that RTS within 2 days of a concussion is associated with improved symptoms, “and may directly or indirectly promote faster recovery,” they concluded.
 

Early return remains feasible for most children and teens

“Return to school can be a complicated issue for children and teens with concussions,” said Caitlyn Mooney, MD, a pediatrician and specialist in sports medicine at the University of Texas Health Science Center, San Antonio, said in an interview. Although much research has focused on diagnosis and return to sport after a concussion, there has been less focus on returning to school and learning. Various issues post concussion can make schooling difficult, and students may experience trouble with vision, concentration, sleep, headaches, and more.

Despite this knowledge, studies that specifically address recommended school protocols are limited, Dr. Mooney said. “Additionally, all concussions are different; while some students will need minimal help to return and succeed in school, others may need individualized learning plans and accommodations for school.” A return to school ideally would be a team-based approach with input from the parent, patient, physician, and educators.

“The theory of cognitive rest stems from the idea that a concussion causes metabolic dysfunction in the brain, and that increasing the metabolic demands of the brain can result in symptoms and a delayed return to school,” said Dr. Mooney.

Evidence suggests that those who start resting early after a concussion improve more quickly, “but there has been ongoing discussion over the years of what is the correct balance of cognitive rest to returning to modified activity,” she said. “This has led to the current general recommendation of rest for 24-48 hours followed by a gradual return to school as tolerated.”

Although the current study is large, it is limited by the lack of randomization, Dr. Mooney noted, therefore conclusions cannot be made that the cause of the improved symptoms is a quicker return to school.

However, the results support data from previous studies, in that both of the older age groups showed less disease burden at 14 days after an earlier return to school, she said.

“With prolonged absences, adolescents get isolated at home away from friends, and they may have increased mood symptoms. Additionally, I have found a high number of my patients who do not go to school as quickly have more sleep disturbance, which seems to increase symptoms such as difficulty concentrating or headaches,” she said. “It seems like the students do benefit from a routine schedule even if they have to have some accommodations at school, especially older students who may have more stress about missing school and falling behind on schoolwork.”

The message for pediatricians is that return to school should be individualized, Dr. Mooney said.

Although the current study does not dictate the optimal return to school, the results support those of previous studies in showing that, after 1-2 days of rest, an early return does not harm children and teens and may improve symptoms in many cases, she said. “In my experience, sometimes schools find it easier to keep the student at home rather than manage rest or special accommodations,” but the current study suggests that delaying return to school may not be the right choice for many patients.

“I hope this study empowers clinicians to advocate for these students, that the right place for them is in the classroom even with rest, extra time, or other accommodations,” said Dr. Mooney.

“Each concussion should be evaluated and treated individually; there will likely be a few who may need to stay home for a longer period of time, but this study suggests that the majority of students will suffer no ill effects from returning to the normal routine after a 2-day rest,” she noted.

The study was supported by the Canadian Institutes for Health Research. Dr. Vaughan and several coauthors disclosed being authors of the Postconcussion Symptom Inventory outside of the current study. Dr. Mooney had no financial conflicts to disclose.

Children and teens with concussions who returned to school sooner showed fewer symptoms after 2 weeks than those who returned to school later, based on data from more than 1,600 individuals aged 5-18 years.

The timing for return to school after a concussion has been the subject of guidelines, but data on how the timing of school returns affects later symptom burdens are limited, Christopher G. Vaughan, PhD, of Children’s National Hospital, Rockville, Md., and colleagues wrote.

Examining how the timing of return to school (RTS) affects later symptoms is needed to inform early postinjury management, they said.

In the new study published in JAMA Network Open, the researchers identified 1,630 children and teens aged 5-18 years who were treated for concussions at nine Canadian pediatric EDs. The primary outcome was symptom burden at 14 days post concussion, based on the Post-Concussion Symptom Inventory (PCSI). Early RTS was defined as missing fewer than 3 days of school post concussion.

Overall, the mean number of missed school days was 3.74 (excluding weekends). When divided by age, the mean number of missed days was 2.61 for children aged 5-7 years, 3.26 for those aged 8-12 years, and 4.71 for those aged 13-18 years.

Slightly more than half (53.7%) of the participants had an early RTS of 2 missed days or fewer. Later RTS was most common in the oldest age group, followed by the middle and younger age groups.

The researchers used a propensity score–matched analysis to determine associations. At 14 days, an early RTS was associated with reduced symptoms among 8- to 12-year-olds and 13- to 18-year-olds, though not in the youngest patients aged 5-7 years. In addition, the researchers created quantiles based on initial symptom ratings.

For the youngest age group, the association between early RTS and reduced symptoms at day 14 was higher among those with lower initial symptoms.

For the two older groups, the association was higher for those with higher initial symptoms (based on the PCSI).

The findings that earlier RTS was associated with a lower symptom burden at day 14 for those with higher levels of symptoms at baseline was surprising, but the mechanisms of the timing and effect of RTS requires more study, the researchers wrote in their discussion.

The effect of early RTS on symptoms may be in part related to factors such as “the benefits of socialization, reduced stress from not missing too much school, maintaining or returning to a normal sleep-wake schedule, and returning to light to moderate physical activity (gym class and recreational activities),” the researchers noted.

Another study related to recovery and concussion recently appeared in Neurology. In that study, the authors found that those athletes who took a longer time to recover from a sports-related concussion could still return to play with additional time off, but the methods and populations differed from the current study, which focused on RTS rather than returning to play.

The current study findings were limited by several factors including the lack of randomization for RTS timing and a lack of data on the variety of potential supports and accommodations students received, the researchers noted.

However, the results were strengthened by the large size and diverse nature of the concussions, and the roughly equal representation of boys and girls, they said.

Although randomized trials are needed to determine the best timing for RTS, the current study suggests that RTS within 2 days of a concussion is associated with improved symptoms, “and may directly or indirectly promote faster recovery,” they concluded.
 

Early return remains feasible for most children and teens

“Return to school can be a complicated issue for children and teens with concussions,” said Caitlyn Mooney, MD, a pediatrician and specialist in sports medicine at the University of Texas Health Science Center, San Antonio, said in an interview. Although much research has focused on diagnosis and return to sport after a concussion, there has been less focus on returning to school and learning. Various issues post concussion can make schooling difficult, and students may experience trouble with vision, concentration, sleep, headaches, and more.

Despite this knowledge, studies that specifically address recommended school protocols are limited, Dr. Mooney said. “Additionally, all concussions are different; while some students will need minimal help to return and succeed in school, others may need individualized learning plans and accommodations for school.” A return to school ideally would be a team-based approach with input from the parent, patient, physician, and educators.

“The theory of cognitive rest stems from the idea that a concussion causes metabolic dysfunction in the brain, and that increasing the metabolic demands of the brain can result in symptoms and a delayed return to school,” said Dr. Mooney.

Evidence suggests that those who start resting early after a concussion improve more quickly, “but there has been ongoing discussion over the years of what is the correct balance of cognitive rest to returning to modified activity,” she said. “This has led to the current general recommendation of rest for 24-48 hours followed by a gradual return to school as tolerated.”

Although the current study is large, it is limited by the lack of randomization, Dr. Mooney noted, therefore conclusions cannot be made that the cause of the improved symptoms is a quicker return to school.

However, the results support data from previous studies, in that both of the older age groups showed less disease burden at 14 days after an earlier return to school, she said.

“With prolonged absences, adolescents get isolated at home away from friends, and they may have increased mood symptoms. Additionally, I have found a high number of my patients who do not go to school as quickly have more sleep disturbance, which seems to increase symptoms such as difficulty concentrating or headaches,” she said. “It seems like the students do benefit from a routine schedule even if they have to have some accommodations at school, especially older students who may have more stress about missing school and falling behind on schoolwork.”

The message for pediatricians is that return to school should be individualized, Dr. Mooney said.

Although the current study does not dictate the optimal return to school, the results support those of previous studies in showing that, after 1-2 days of rest, an early return does not harm children and teens and may improve symptoms in many cases, she said. “In my experience, sometimes schools find it easier to keep the student at home rather than manage rest or special accommodations,” but the current study suggests that delaying return to school may not be the right choice for many patients.

“I hope this study empowers clinicians to advocate for these students, that the right place for them is in the classroom even with rest, extra time, or other accommodations,” said Dr. Mooney.

“Each concussion should be evaluated and treated individually; there will likely be a few who may need to stay home for a longer period of time, but this study suggests that the majority of students will suffer no ill effects from returning to the normal routine after a 2-day rest,” she noted.

The study was supported by the Canadian Institutes for Health Research. Dr. Vaughan and several coauthors disclosed being authors of the Postconcussion Symptom Inventory outside of the current study. Dr. Mooney had no financial conflicts to disclose.

Children and teens with concussions who returned to school sooner showed fewer symptoms after 2 weeks than those who returned to school later, based on data from more than 1,600 individuals aged 5-18 years.

The timing for return to school after a concussion has been the subject of guidelines, but data on how the timing of school returns affects later symptom burdens are limited, Christopher G. Vaughan, PhD, of Children’s National Hospital, Rockville, Md., and colleagues wrote.

Examining how the timing of return to school (RTS) affects later symptoms is needed to inform early postinjury management, they said.

In the new study published in JAMA Network Open, the researchers identified 1,630 children and teens aged 5-18 years who were treated for concussions at nine Canadian pediatric EDs. The primary outcome was symptom burden at 14 days post concussion, based on the Post-Concussion Symptom Inventory (PCSI). Early RTS was defined as missing fewer than 3 days of school post concussion.

Overall, the mean number of missed school days was 3.74 (excluding weekends). When divided by age, the mean number of missed days was 2.61 for children aged 5-7 years, 3.26 for those aged 8-12 years, and 4.71 for those aged 13-18 years.

Slightly more than half (53.7%) of the participants had an early RTS of 2 missed days or fewer. Later RTS was most common in the oldest age group, followed by the middle and younger age groups.

The researchers used a propensity score–matched analysis to determine associations. At 14 days, an early RTS was associated with reduced symptoms among 8- to 12-year-olds and 13- to 18-year-olds, though not in the youngest patients aged 5-7 years. In addition, the researchers created quantiles based on initial symptom ratings.

For the youngest age group, the association between early RTS and reduced symptoms at day 14 was higher among those with lower initial symptoms.

For the two older groups, the association was higher for those with higher initial symptoms (based on the PCSI).

The findings that earlier RTS was associated with a lower symptom burden at day 14 for those with higher levels of symptoms at baseline was surprising, but the mechanisms of the timing and effect of RTS requires more study, the researchers wrote in their discussion.

The effect of early RTS on symptoms may be in part related to factors such as “the benefits of socialization, reduced stress from not missing too much school, maintaining or returning to a normal sleep-wake schedule, and returning to light to moderate physical activity (gym class and recreational activities),” the researchers noted.

Another study related to recovery and concussion recently appeared in Neurology. In that study, the authors found that those athletes who took a longer time to recover from a sports-related concussion could still return to play with additional time off, but the methods and populations differed from the current study, which focused on RTS rather than returning to play.

The current study findings were limited by several factors including the lack of randomization for RTS timing and a lack of data on the variety of potential supports and accommodations students received, the researchers noted.

However, the results were strengthened by the large size and diverse nature of the concussions, and the roughly equal representation of boys and girls, they said.

Although randomized trials are needed to determine the best timing for RTS, the current study suggests that RTS within 2 days of a concussion is associated with improved symptoms, “and may directly or indirectly promote faster recovery,” they concluded.
 

Early return remains feasible for most children and teens

“Return to school can be a complicated issue for children and teens with concussions,” said Caitlyn Mooney, MD, a pediatrician and specialist in sports medicine at the University of Texas Health Science Center, San Antonio, said in an interview. Although much research has focused on diagnosis and return to sport after a concussion, there has been less focus on returning to school and learning. Various issues post concussion can make schooling difficult, and students may experience trouble with vision, concentration, sleep, headaches, and more.

Despite this knowledge, studies that specifically address recommended school protocols are limited, Dr. Mooney said. “Additionally, all concussions are different; while some students will need minimal help to return and succeed in school, others may need individualized learning plans and accommodations for school.” A return to school ideally would be a team-based approach with input from the parent, patient, physician, and educators.

“The theory of cognitive rest stems from the idea that a concussion causes metabolic dysfunction in the brain, and that increasing the metabolic demands of the brain can result in symptoms and a delayed return to school,” said Dr. Mooney.

Evidence suggests that those who start resting early after a concussion improve more quickly, “but there has been ongoing discussion over the years of what is the correct balance of cognitive rest to returning to modified activity,” she said. “This has led to the current general recommendation of rest for 24-48 hours followed by a gradual return to school as tolerated.”

Although the current study is large, it is limited by the lack of randomization, Dr. Mooney noted, therefore conclusions cannot be made that the cause of the improved symptoms is a quicker return to school.

However, the results support data from previous studies, in that both of the older age groups showed less disease burden at 14 days after an earlier return to school, she said.

“With prolonged absences, adolescents get isolated at home away from friends, and they may have increased mood symptoms. Additionally, I have found a high number of my patients who do not go to school as quickly have more sleep disturbance, which seems to increase symptoms such as difficulty concentrating or headaches,” she said. “It seems like the students do benefit from a routine schedule even if they have to have some accommodations at school, especially older students who may have more stress about missing school and falling behind on schoolwork.”

The message for pediatricians is that return to school should be individualized, Dr. Mooney said.

Although the current study does not dictate the optimal return to school, the results support those of previous studies in showing that, after 1-2 days of rest, an early return does not harm children and teens and may improve symptoms in many cases, she said. “In my experience, sometimes schools find it easier to keep the student at home rather than manage rest or special accommodations,” but the current study suggests that delaying return to school may not be the right choice for many patients.

“I hope this study empowers clinicians to advocate for these students, that the right place for them is in the classroom even with rest, extra time, or other accommodations,” said Dr. Mooney.

“Each concussion should be evaluated and treated individually; there will likely be a few who may need to stay home for a longer period of time, but this study suggests that the majority of students will suffer no ill effects from returning to the normal routine after a 2-day rest,” she noted.

The study was supported by the Canadian Institutes for Health Research. Dr. Vaughan and several coauthors disclosed being authors of the Postconcussion Symptom Inventory outside of the current study. Dr. Mooney had no financial conflicts to disclose.