Researchers and data scientists at UT Southwestern Medical Center and MD Anderson Cancer Center have developed an artificial intelligence technique that can identify which cell surface peptides produced by cancer cells called neoantigens are recognized by the immune system.
The pMTnet technique, detailed online in Nature Machine Intelligence, could lead to new ways to predict cancer prognosis and potential responsiveness to immunotherapies.
“Determining which neoantigens bind to T cell receptors and which don’t has seemed like an impossible feat. But with machine learning, we’re making progress,” said senior author Dr. Tao Wang, Ph.D., Assistant Professor of Population and Data Sciences, and with the Harold C. Simmons Comprehensive Cancer Center and the Center for Genetics of Host Defense at UT Southwestern.
Mutations in the genome of cancer cells cause them to display different neoantigens on their surfaces. Some of these neoantigens are recognized by immune T cells that hunt for signs of cancer and foreign invaders, allowing cancer cells to be destroyed by the immune system. However, others seem invisible to T cells, allowing cancers to grow unchecked.
“For the immune system, the presence of neoantigens is one of the biggest differences between normal and tumor cells,” said Tianshi Lu, first co-author with Ze Zhang, doctoral students in the Tao Wang lab, which uses state-of-the-art bioinformatics and biostatistics approaches to study the implications of tumor immunology for tumorigenesis, metastasis, prognosis, and treatment response in a variety of cancers. “If we can figure out which neoantigens stimulate an immune response, then we may be able to use this knowledge in a variety of different ways to fight cancer,” Ms. Lu said.
Being able to predict which neoantigens are recognized by T cells could help researchers develop personalized cancer vaccines, engineer better T cell-based therapies, or predict how well patients might respond to other types of immunotherapies. But there are tens of thousands of different neoantigens, and methods to predict which ones trigger a T cell response have proven to be time-consuming, technically challenging, and costly.
Searching for a better technique with support of grants from the National Institutes of Health (NIH) and Cancer Prevention and Research Institute of Texas (CPRIT), the research team looked to machine learning. They trained a deep learning-based algorithm that they named pMTnet using data from known binding or nonbinding combinations of three different components: neoantigens; proteins called major histocompatibility complexes (MHCs) that present neoantigens on cancer cell surfaces; and the T cell receptors (TCRs) responsible for recognizing the neoantigen-MHC complexes. They then tested the algorithm against a dataset developed from 30 different studies that had experimentally identified binding or nonbinding neoantigen T cell-receptor pairs. This experiment showed that the new algorithms had a high level of accuracy.
The researchers used this new tool to gather insights on neoantigens cataloged in The Cancer Genome Atlas, a public database that holds information from more than 11,000 primary tumors. pMTnet showed that neoantigens generally trigger a stronger immune response compared with tumor-associated antigens. It also predicted which patients had better responses to immune checkpoint blockade therapies and had better overall survival rates.
“As an immunologist, the most significant hurdle currently facing immunotherapy is the ability to determine which antigens are recognized by which T cells in order to leverage these pairings for therapeutic purposes,” said corresponding author Alexandre Reuben, Ph.D., Assistant Professor of Thoracic-Head & Neck Medical Oncology at MD Anderson. “pMTnet outperforms its current alternatives and brings us significantly closer to this objective.”
Other UTSW researchers who contributed to this study include James Zhu, Yunguan Wang, Xue Xiao, and Lin Xu. Other MD Anderson scientists who contributed to this work include Peixin Jiang, Chantale Bernatchez, John V. Heymach, and Don L. Gibbons. Dr. Jun Wang from NYU Langone Health also contributed to this work.
UT Southwestern’s Simmons Cancer Center and MD Anderson Cancer Center are among the exclusive 51 designated comprehensive centers with the National Cancer Institute, which includes a joint effort with the National Human Genome Research Institute to oversee The Cancer Genome Atlas project. The study was supported by the NIH (grants 5P30CA142543/TW and R01CA258584/TW), CPRIT (RP190208/TW), MD Anderson (Lung Cancer Moon Shot), the University Cancer Foundation at MD Anderson, the Waun Ki Hong Lung Cancer Research Fund, Exon 20 Group, and Rexanna’s Foundation for Fighting Lung Cancer.

Scientists at La Jolla Institute for Immunology (LJI) have published a detailed map of where human antibodies bind to SARS-CoV-2, a map that was generated by a global collaboration comparing nearly all leading clinical candidates. The new research, published in Science, will guide the development of more effective COVID-19 antibody therapies and help scientists develop effective vaccines to address emerging viral variants.
The findings propel COVID-19 research in three key ways: Hundreds of antibodies contributed by over 50 different organizations around the world were classified and mapped. This study shows exactly where each antibody binds on the Spike protein of SARS-CoV-2. The researchers describe the neutralizing strength, or potency, of each antibody and the likelihood that each antibody could offer protection against viral variants. Antibodies with similar footprints on Spike were grouped into “communities.” The researchers show how antibodies from different communities could be combined in a powerful antibody “cocktail” to target the virus.”We were able to map the geography of Spike and understand which antibodies bind to which footprints. This map provides a reference to help predict which antibodies are still effective against SARS-CoV-2 variants of concern like the currently surging Delta variant,” says LJI Professor Erica Ollmann Saphire, Ph.D., who leads the global effort behind this research, called the Coronavirus Immunotherapeutic Consortium (CoVIC).
In fact, the researchers found three different groups of antibodies that are resistant to mutations in SARS-CoV-2 Spike protein. These antibodies could target vulnerable sites on the Spike protein, even as it mutates.
“We now have a framework for selecting durable antibody cocktails for COVID-19 treatment,” says Saphire.
Gathering powerful antibodies
The CoVIC includes about 370 antibodies from 59 different discovery efforts that cover a broad range: from academic labs and small biotechs to large international pharmaceutical corporations. These antibody therapeutics are being evaluated side-by-side in standardized lab by seven different partner labs. The Saphire team at LJI is determining high-resolution structures of these antibodies and also rapidly generated tools to examine the effects of mutations in Spike on antibody potency.

SharecloseShare pageCopy linkAbout sharingimage source, Getty ImagesA 12-year-old boy in the Dutch city of Groningen has won a court battle to get vaccinated against Covid-19 so that he can visit his dying grandmother, despite his father’s objections.A judge ruled the jab would reduce his chances of passing on any infection to the woman, who has advanced cancer.Vaccines have been approved for Dutch 12-17-year-olds but under-17s need the consent of both parents.Vaccine scepticism is increasing in the country.Judge Bart Tromp of Groningen District Court said that the boy should be vaccinated promptly because his interests were more important than the father’s concerns.Court papers said the boy wanted to spend as much time as possible with his grandmother, who has metastatic lung cancer and is “in the last stages of her life”.Judge Tromp rejected arguments by the boy’s father that vaccines were “in a test phase” and posed risks to reproductive organs, saying they had no scientific basis.He also cited risks that, while children were less likely to be severely ill with the virus, they could develop long Covid.The risk of infecting others was also lower, he said.The boy’s mother has supported his court action. The couple are divorced.Dutch law says that if the parents cannot agree, a judge should rule in the best interests of the child.

The most common method of assessing the condition may make Black patients seem less ill than they really are, some experts say. A new report calls for scrapping the formula.A scientific task force on Thursday called for jettisoning a common measure of kidney function that adjusts results by race, providing different assessments for Black patients than for others.The adjustment may make Black patients seem less ill than they really are, according to many experts. Instead, doctors should rely on a race-neutral method for diagnosing and managing kidney disease, concluded a report from the National Kidney Foundation and the American Society of Nephrology.The specific equation recommended was described in a study published Thursday in the New England Journal of Medicine.If adopted, the new approach would affect hundreds of millions of kidney function tests performed yearly in hospitals and outpatient settings, both for acutely ill patients and as part of routine screening blood tests. By one estimate, one million Black Americans might be treated earlier for kidney disease if the diagnostic equation were not adjusted for race.The task force report, published concurrently in the American Journal of Kidney Diseases and the Journal of the American Society of Nephrology, comes amid a national reckoning over racial health disparities spurred by the Covid-19 pandemic, which has taken a disproportionate toll on people of color and has highlighted the excessive burdens of chronic disease in those communities.“The issue is a moral issue,” said Dr. Neil R. Powe, co-chair of the task force and chief of medicine at Zuckerberg San Francisco General Hospital and Trauma Center. “It is time to remove race from the equation.”Black and Hispanic Americans have long suffered from high rates of conditions such as diabetes, high blood pressure and obesity, which can exacerbate a bout of Covid. These factors can also increase the risk of developing kidney disease.The racial disparities in kidney disease are stark and well documented. Black Americans are more than three times as likely as white Americans to experience kidney failure and require dialysis or a kidney transplant.Though Black Americans make up only 13 percent of the population, they represent 35 percent of Americans with kidney failure. More than 90,000 Americans are on a waiting list for a kidney; nearly one-third are Black, about as many as those who are white.People of color and low-income Americans are less likely to receive good care when the warning signs first appear and chronic kidney disease could be prevented. They are more likely to progress to kidney failure and to require dialysis, and less likely to be cared for by a kidney specialist before getting to that stage, according to a report by the Centers for Medicare and Medicaid Services.Black Americans also wait longer for an organ, and are less likely to have a kidney donated by a friend or relative, for a variety of complex reasons.“This new recommendation will ensure that racial biases are not introduced to clinical care, so someone will no longer be judged based on their race and have their skin color dictate what kidney care they receive,” said Dr. Nwamaka Denise Eneanya, a nephrologist at the University of Pennsylvania and a member of the task force.Her work suggests that current measures used to assess kidney function may underestimate the severity of illness in Black patients, delaying referrals to specialists and making them less likely to be placed on waiting lists for a kidney transplant.“Black individuals are inadvertently harmed because they are seen as not sick enough,” Dr. Eneanya said.Other task force members cautioned that the impact of the change on patient outcomes was uncertain, and called on researchers to follow up to evaluate its impact.The use of medical decision-making tools that take race and ethnicity into account is not unique to kidney disease. Algorithms and calculators that doctors rely on to guide diagnosis and treatment for many conditions — from bone density and kidney stones, to cancer and pulmonary function tests — include race as a variable, as outlined in a paper published last year in the New England Journal of Medicine.“Race is a social construct and not a biological one,” said Dr. Winfred Williams, associate chief of the renal division at Massachusetts General Hospital in Boston, who co-wrote an editorial on the new equations.“It may be serving as a proxy for other risk factors including food insecurity, housing insecurity, socioeconomic deprivation, all of which can limit access to best health care practices.”In recent months, several medical societies have taken steps to address the potential bias. In May, the American Academy of Pediatrics officially dropped a practice guideline that considered the race of a baby when evaluating the risk of a urinary tract infection.The American College of Obstetricians and Gynecologists is currently updating an algorithm that has included race and ethnicity in a calculator used to assess the chances a pregnant woman will have a successful vaginal birth after a previous cesarean section.The new report that reassessed the inclusion of race in the diagnosis of kidney diseases was issued Thursday, after a year of work and no small degree of controversy along the way, the authors said.The kidneys filter toxins from the blood. The new report recommends using a new equation to estimate the filtration rate using a blood test that measures levels of creatinine, a waste product made by muscles that is kept in check when the kidneys are functioning properly.A related study, also published Thursday in the New England Journal of Medicine and cited in the report, developed and evaluated new diagnostic methods that do not include race as a variable. The researchers concluded that the new creatinine equation could be adopted immediately.But the most accurate, race-neutral way to measure kidney filtration rates would incorporate blood tests that measure the level of a different marker: a protein produced by cells called cystatin C, which is elevated when kidneys are not functioning well, researchers said.Tests of cystatin C are more expensive and not as widely available, but experts called for making them more accessible and gradually increasing their use.

Cancer cells proliferate despite a myriad of stresses — from oxygen deprivation to chemotherapy — that would kill any ordinary cell. Now, researchers at UC San Francisco have gained insight into how they may be doing this through the downstream activity of a powerful estrogen receptor. The discovery offers clues to overcoming resistance to therapies like tamoxifen that are used in many types of breast cancer.
Estrogen receptor α (ERα) drives more than 70 percent of breast cancers. The new research published Sept. 23, 2021, in Cell discovered that in addition to its well-known activity in the nucleus, it can also help malignant cells overcome innate anti-cancer mechanisms and develop resistance to treatment.
In the nucleus, ERα regulates the conversion of DNA to messenger RNA (mRNA), a process known as transcription. Once formed, the mRNA strand travels from the nucleus into the cytoplasm, where it instructs ribosomes to make protein, a process known as translation. To their surprise, the researchers found that ERα plays a role in this process as well by binding to the newly formed mRNA.
“The RNA-centric function of the estrogen receptor has so far been hidden behind its well-established role as a transcription factor, and may have been supporting cancer progression on the sly,” said Yichen Xu, PhD, a postdoctoral fellow in urology at UCSF and the first author of the study.
A New Role for ER?
Using breast cancer cell lines, the research team saw how ERα tends to bind to RNAs, particularly messenger RNAs (mRNAs) involved in cancer progression. Some of these mRNAs keep cells from committing suicide when they accumulate too many harmful mutations. Others help them proliferate under extremely difficult conditions, such as lack of oxygen or nutrients. Still others help them evade therapeutic interventions.

The master regulator behind the development of antibody-producing cells has been identified in a study by investigators at Weill Cornell Medicine. The findings provide new insight into the inner workings of the immune system and may help understand how tissues develop and how certain cancers arise.
The study, published Sept. 23 in Nature Immunology, combined computational analyses with advanced molecular biology and genomic techniques to identify a protein called Oct2 as the key determinant of the B-cell humoral immune response.
During an infection or after a vaccination, mature B cells form germinal centers, a sort of pop-up training facility. There, the cells mutate and rearrange their antibody-encoding genes, until they either produce an improved antibody or die trying. The process is central to the body’s responses to many pathogens, but it’s also fraught with danger; poorly-placed B cell mutations can cause lymphoid cancers.
“All of our cells have defense mechanisms against becoming mutated, but B cells actually do the opposite; they specialize in mutating, and they do it very fast,” said co-senior author Dr. Ari Melnick, the Gebroe Family Professor of Hematology / Oncology and a member of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine.
Previous studies showed that B cells control their germinal center maturation by altering the accessibility of different parts of their genomes, and triggering cascades of gene expression changes to direct and limit their development. But what coordinates all of those signals?
To answer that question, Weill Cornell Graduate School of Medical Sciences student Ashley Doane, along with colleagues at Weill Cornell Medicine and The Rockefeller University, first took a computational approach, mapping all the gene regulation changes maturing B cells undergo.

In a study with mice reported today in the journal Science Translational Medicine, a Johns Hopkins Medicine research team has provided what may be the most definitive view to date of the biological process leading to necrotizing enterocolitis (NEC), a dangerous inflammatory disease that can destroy a premature infant’s intestinal lining and causes death in up to a third of the cases. The researchers showed that the loss of enteric glia — cells that support specialized nerves in the intestine — leads to intestinal dysmotility — a condition in which the gastrointestinal tract loses its ability to move food and other materials along (known as peristalsis) — and that this malfunction is a key factor in the genesis of NEC.
“Symptoms seen in premature infants, such as a distended abdomen and intolerances to foods — the things that result from intestinal dysmotility — have traditionally been considered consequences of NEC,” says study senior author David Hackam, M.D., Ph.D., surgeon-in-chief at Johns Hopkins Children’s Center and professor of surgery at the Johns Hopkins University School of Medicine. “Our findings suggest, perhaps for the first time, that these conditions may actually be a cause, rather than just a result, of NEC.”
Hackam and his colleagues say it seems logical that the enteric nervous system and the glial cells supporting its function play such a pivotal role in NEC’s genesis. “This system has been called ‘the body’s second brain’ because of its importance to overall health,” he says.
In their study, the researchers also found that overproduction of a protein called toll-like receptor 4 (TLR4) — shown in previous Johns Hopkins Medicine studies to be involved in NEC’s onset — triggers the enteric glia loss. In separate experiments, they demonstrated that inhibiting TLR4 and ensuring enteric glia survival enables the cells to produce a growth factor called brain-dependent neurotrophic factor (BDNF), which in turn curtails the wayward immune response leading to NEC.
“This finding enabled us to test in mice the use of a compound that could ‘kick-start’ the intestine by preserving enteric glia and their ability to produce BDNF, resulting in restored intestinal movement — and most importantly, the prevention of NEC,” says study lead author Mark Kovler, M.D., a general surgery resident at the Johns Hopkins University School of Medicine.
Seen in as many as 12% of newborn babies born before 37 weeks gestation, NEC is a rapidly progressing gastrointestinal emergency in which normally harmless gut bacteria invade the underdeveloped wall of the premature infant’s colon, causing inflammation that can ultimately destroy healthy tissue at the site. If enough cells become necrotic (die) so that a hole is created in the intestinal wall, harmful bacteria can enter the bloodstream and cause life-threatening sepsis.
In earlier mouse studies, the Johns Hopkins Medicine researchers showed that NEC results when the underdeveloped intestinal lining in premature infants produces higher-than-normal amounts of TLR4. TLR4 in full-term babies binds with bacteria in the gut and helps keep threatening microbes in check. However, in premature infants, TLR4 can act like an immune system switch, with excess amounts of the protein mistakenly directing the body’s disease defense mechanism against the intestinal wall instead.
“Knowing this, we designed our current study to see if TLR4 was involved in the loss of enteric glia, and if so, how that might pave the way for NEC to develop,” says Kovler.
As a result of their experiments, the researchers were able to provide five lines of evidence that intestinal dysmotility — as a consequence of TLR4-influenced loss of enteric glia — is a critical factor in the development of NEC: Three different strains of mice bred without enteric glia showed impaired intestinal movement, and in turn, more severe NEC, than wild-type (genetically normal) mice. Mice bred with enteric glia that cannot produce TLR4 did not lose glial cells, show dysmotility or develop NEC, indicating that TLR4 is necessary for glial cell loss and its link to the disease. Giving BDNF to glial-deficient mice reduced the severity of NEC in the animals, suggesting that BDNF release from enteric glia helps the cells protect the intestine from NEC. When too much TLR4 is present in the intestinal wall, the release of BDNF prevents the overabundant protein from signaling the immune system to mistakenly attack healthy tissues. Oxolinic acid (designated compound J11 by the Johns Hopkins Medicine team), a synthetic antibiotic developed in Japan and used in veterinary medicine, was found to enhance BDNF release from enteric glia, restore intestinal movement and reduce the severity of NEC in wild-type mice. By comparison — and as expected — it didn’t work in mice lacking enteric glia and unable to produce BDNF.The researchers also studied NEC-damaged intestinal tissues taken from wild-type mice, piglets and human infants (whose tissues had been removed during surgery to treat NEC), finding in all cases that enteric glia were depleted.
“Because we have shown that enteric glia protect animal intestines from the devastating effects of NEC, it is reasonable to assume a similar scenario exists in humans,” says Hackam. “And if we can one day repair the system when it’s broken and prevent NEC in premature infants — through the use of enteric glia therapies such as J11 — then that will be one less obstacle for these tiny patients to overcome.”
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COVID-19 disease severity seems to be affected by the characteristics of white blood cells called granulocytes, which are part of the innate immune system. Combined measurements of granulocytes and well-known biomarkers in the blood can predict the severity of the disease, according to a new study from Karolinska Institutet in Sweden. The results are published in the Proceedings of the National Academy of Sciences and may eventually contribute to more tailored treatments for COVID-19 patients.
Granulocytes are a family of white blood cells that include neutrophils, eosinophils and basophils. They are part of the so-called innate immune system, which is the body’s first line of defence against pathogens. There are many studies on how SARS-CoV-2 affects various components of the immune system, but there is still a lack of knowledge about the role of granulocytes in COVID-19.
Researchers at Karolinska Institutet have now investigated the characteristics of granulocytes in the blood during the early phase of SARS-CoV-2 infection in a total of 26 hospitalised patients with COVID-19 at the Karolinska University Hospital. They also performed follow-up analyses four months after hospital discharge and compared these with analyses of healthy uninfected individuals.
“Our study shows significantly altered characteristics of all granulocyte subsets in COVID-19 patients and this can be linked to the severity of the disease,” says lead author Magda Lourda, who is a researcher at the Department of Medicine, Huddinge, at Karolinska Institutet.
Combined measurements of granulocyte characteristics and widely used biomarkers in the blood called C-reactive protein (CRP) and creatinine, could predict key clinical features such as respiratory function and multiorgan failure.
“The finding needs to be taken with caution considering the limited size of our study cohort, but our hope is that these combined measurements can be used to predict the severity of the disease, resulting in more tailored treatments for COVID-19 patients,” says Magda Lourda.
The study is part of the Karolinska KI/K COVID-19 Immune Atlas project, which was initiated in April 2020, aiming at providing a comprehensive overview of the immune response to SARS-CoV-2 in hospitalised patients with moderate or severe COVID-19.
The study was supported by grants from Nordstjernan AB, Knut and Alice Wallenberg Foundation, the Swedish Governmental Agency for Innovation Systems, the Swedish Research Council, the Swedish Cancer Foundation, Clas Groschinsky Foundation, the Center for Innovative Medicine at Karolinska Institutet, the Swedish Children’s Cancer Foundation, Dr Åke Olsson Foundation and Karolinska Institutet’s research foundation. Part of the data handling and analysis was enabled by resources provided by the Swedish National Infrastructure for Computing.
Co-author Karl-Johan Malmberg is a scientific advisor and has a research grant from Fate Therapeutics and is a member of the scientific advisory board of Vycellix Inc. Hans-Gustaf Ljunggren is a member of the board of XNK Therapeutics AB and Vycellix Inc. Jan-Inge Henter serves as consultant for Sobi AB.
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The nucleus of a cell fills a crucial function: to protect cell DNA and enable its proper use. But it can be deformed, or even temporarily fractured, if the cell itself is compressed and deformed, for example, in the case of migration or proliferation. This compression then leads to DNA damage. The consequences are accelerated ageing for healthy cells and the acquisition of invasive properties for breast tumour cells, as has just been shown by a research team from CNRS, Institut Curie and INSERM1.
These scientists have shown that when cells are compressed and that breaks the nucleus, DNA can come into contact with a DNA-destroying enzyme called TREX1. TREX1’s normal function is to protect the cell by destroying the DNA of viruses that try to infect it, but under these unusual conditions it attacks the cell DNA.
In healthy tissue, the cells then show signs of ageing and stop dividing. However, the research team has observed that the consequences are different in a breast tumour: instead of killing the cancer cells, the damage caused by TREX1 will make them more invasive. For example, when the tumour grows too much, the cells are compressed and then acquire the ability to destroy their environment to invade neighbouring tissues, with increased risk of metastasis.
These results reveal the importance of the enzyme TREX1 in the development of breast cancer and also in ageing. The scientists now want to identify and test molecules that could block its activity. Because TREX1 has an important role in modulating inflammation and immunity, these inhibitors may have many applications in therapy.
Notes
1- In France, researchers from the Laboratoire Biologie Cellulaire et Cancer (CNRS/Institut Curie/Sorbonne Université), the Laboratoire Immunité et Cancer (INSERM/Institut Curie), the Laboratoire Physico-chimie Curie (CNRS/Sorbonne Université/Institut Curie), the Laboratoire Processus d’Activation Sélectif par Transfert d’Energie Uni-électronique ou Radiatif (CNRS/ENS — PSL/Sorbonne Université) and the Centre de Recherche des Cordeliers (INSERM/Université de Paris/Sorbonne Université) participated in this work.
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Children who experience sexual or physical abuse or are neglected are more likely to die prematurely as adults, according to a new study analysing data from the 1950s to the present by researchers at UCL and the University of Cambridge.
The study, published in BMJ Open, found that adults who reported experiencing sexual abuse by the age of 16 had a 2.6 times higher risk of dying in middle age — that is, between 45 and 58 — than those who did not report sexual abuse.
Adults who reported experiencing physical abuse by 16, meanwhile, had a 1.7 times higher risk of premature death, while those who experienced neglect — assessed using questionnaire responses gathered from parents and teachers of respondents during childhood — had a 1.4 times higher risk.
The researchers also looked at the link between early-life socioeconomic disadvantage and early death. They found that those who were disadvantaged at birth (that is, those whose father’s job was classed as unskilled manual labour) had a 1.9 times higher risk of premature mortality than other socioeconomic groups.
The study was based on data from 9,310 people born in 1958 who are part of the 1958 National Child Development Study, a nationally representative birth cohort study.
First author Dr Nina Rogers, who led the work while at UCL and is now at the University of Cambridge, said: “Our work shows the long-lasting consequences that specific types of child abuse and neglect can have. The findings are especially important because these early-life adversities are not uncommon, affecting millions of people in the UK.”*
The researchers examined socioeconomic and health-related factors that might explain why people who were abused or neglected as children, or who were born at an economic disadvantage, were more likely to die in middle age. They found that smoking appeared to be especially important in explaining mortality among those who were physically abused or neglected, and among those who were economically disadvantaged.