Researchers analyzed 120 previous clinical trials, finding no evidence that treatment efficacies depend on number of comorbidities. Peter Hanlon (CC-BY 4.0, https://creativecommons.org/licenses/by/4.0/)
Treatment efficacy for a broad range of chronic diseases does not differ depending on patients’ comorbidities, according to a new study publishing June 6thin the open access journal PLOS Medicine by David McAllister of the University of Glasgow, UK, and colleagues.
There is often uncertainty about how treatments for single conditions should be applied to people who have multiple chronic conditions (multimorbidity). This confusion stems, in part, from the fact that people with multimorbidity are under-represented in randomized controlled trials, and trials rarely report whether the efficacy of treatment differs by the number of comorbidities or the presence of specific comorbidities.
In the new study, the researchers used existing data from 120 industry-sponsored randomized controlled phase 3 and 4 clinical trials carried out between 1990 and 2017. The dataset included a total of 128,331 participants and spanned 23 common long-term conditions, including asthma, diabetes, hypertension, osteoporosis, and migraine. For each trial as well as each treatment type spanning multiple trials, the team modeled whether there were any interactions between treatment efficacy and comorbidities.
Across trials, the percentage of participants with three or more comorbidities ranged from 2.3% (in allergic rhinitis trials) to 57% (in trials for systemic lupus erythematosus). Overall, the new study found no evidence of comorbidities modifying treatment efficacy across any of the 23 conditions studied. However, the authors noted that the trials were not designed to assess variation in treatment efficacy by comorbidity.
“The standard assumption used in evidence syntheses is that efficacy is constant across subgroups, although this is often criticized,” the authors say. “Our findings suggest that for modest levels of comorbidities, this assumption is reasonable.”
Coauthor Peter Hanlon adds, “Many people live with multiple long-term conditions, however deciding on the most appropriate treatment for these people is often challenging because clinical trials rarely report whether treatments work as well in people with multiple conditions and clinical guidelines rarely address the specific needs of these people. We found that treatments had similar effects in people with multiple conditions, which is important as this information can be used to help experts decide which treatments they should recommend in clinical guidelines.”
A new study from Keck Medicine of USC shows that metabolic syndrome, a cluster of conditions that raise the risk of heart disease, diabetes, stroke and other health problems, more than doubles the risk of advanced liver disease among heavy drinkers
Two people regularly have a few alcoholic drinks daily. One develops liver disease. The other doesn’t.
What explains the different outcomes?
The answer may lie in a condition known as metabolic syndrome, a cluster of conditions that together raise the risk of coronary heart disease, diabetes, stroke and other serious health problems. This syndrome, characterized by symptoms such as abdominal fat, high blood pressure, high cholesterol and high blood sugar, affects more than one in three Americans.
A new study from Keck Medicine of USC published in the Annals of Internal Medicine shows that heavy alcohol use may be dramatically more damaging to the liver for people with metabolic syndrome.
“Our research suggests that metabolic syndrome and alcohol interact in such a way that they multiply the effect of alcohol on the liver, more than doubling the risk of advanced liver disease among heavy drinkers,” said Brian P. Lee, MD, MAS, a hepatologist and liver transplant specialist with Keck Medicine who is the lead author on the study. “Drinking is harmful to the liver, but especially so for this segment of the population.”
In the study, heavy alcohol use was defined as two drinks (a total of 12 fluid ounces) a day for women and three drinks (a total of 18 fluid ounces) per day for men.
Lee and his colleagues were motivated to research a connection between advanced liver disease, alcohol use and metabolic syndrome after noticing that between 2009-2018, deaths from alcohol-associated liver disease surged in the United States by more than 30% while alcohol use, including heavy drinking, remained stable or declined.
During the last 20 years, the number of Americans with metabolic syndrome increased significantly. Previous research has shown that metabolic syndrome can cause liver abnormalities.
“We therefore hypothesized that metabolic syndrome could be an important contributor to this unexplained surge in advanced liver disease,” said Lee.
For the study, Lee and his fellow researchers used data from the National Health and Nutrition Examination Survey, which assesses the health and nutritional status of adults and children in the United States, pulling together samples representing the U.S. population 20 years or older between 1999 and 2018.
While the data revealed a slight increase in advanced liver disease with heavy alcohol use without metabolic syndrome, the greatest increase in advanced liver disease was found in those with combined heavy alcohol use and metabolic syndrome.
Lee believes that the increased risk of liver damage from drinking is a result of an increase in the amount of fat in the liver. A healthy liver contains less than five percent fat; any more than that can lead to inflammation and cirrhosis (scarring) of the liver, liver cancer and liver failure.
“Both metabolic syndrome and drinking increase liver fat, and we think that the combination of the two accelerates the accumulation of fat in the liver and fuels inflammation, resulting in a greater chance of liver disease,” said Lee.
He hopes the study will encourage physicians who screen and diagnose patients with metabolic syndrome to also ask about alcohol use and look for liver disease.
“Our study indicates that these conditions may often coexist, and it is in patients’ best interest to address both issues,” he said. “It’s also important for people with metabolic syndrome to realize they may be at an increased likelihood of advanced liver disease, and to monitor their drinking accordingly,” he added.
Mitochondria (green) within a cell are depicted in this colorized transmission electron micrograph. The folds are called cristae, and are where chemical reactions occur that produce energy for cellular and metabolic functions. CREDIT Thomas Deerinck, National center for Microscopy and Imaging Research, UC San DIego
In a wide-ranging paper, a UC San Diego physician-scientist explains why all chronic diseases, from diabetes to autism, are linked by the underlying failure of cells and the body to heal completely
In medicine and science, the term “pathogenesis” describes the origin and development of disease. There is not, however, a broadly accepted term to describe the other half of the equation: the process of healing and recovery.
In a new and far-reaching paper, published May 10, 2023 in the journal Mitochondrion, Robert K. Naviaux, MD, PhD, professor of Medicine, Pediatrics and Pathology at UC San Diego School of Medicine, proposes both a term and, more importantly, outlines the array of processes and players, beginning with cellular mitochondria, that drive the healing process – and whose dysfunction underlies chronic illnesses from diabetes and autoimmune disorders to long COVID and autism spectrum disorder.
“Great strides in medicine since World War II have focused on and addressed the triggers and risk factors of disease,” said Naviaux. “This pathogenesis-based approach has been very effective in developing treatments for acute illnesses, such as those caused by physical trauma, infection, vitamin deficiencies and poisoning.”
The greater health threat now, he said, lies with chronic disease. Six in 10 adults in the United States have a chronic disease; 4 in 10 have two or more. These conditions, such as heart disease, cancer, diabetes, Alzheimer’s and chronic kidney failure, account for 7 out of 10 deaths in the U.S. each year, according to the Centers for Disease Control and Prevention.
“In the last 70 years, not a single chronic illness is curable using current medical paradigms unless it has a cause that can be bypassed, killed, burned out or cut out,” said Naviaux.
“When cures are achieved, they rely on recovery by spontaneous healing — an essential process that operates silently in the background and is still poorly understood. Antibiotics can cure a pneumococcal pneumonia and a stent can reopen an occluded (blocked) coronary artery, but active healing is required after the intervention to repair the damaged lung and heart.
“Without healing,” said Naviaux, “multicellular life on Earth would not exist. Without healing, one injury predisposes to another, leading to disability, chronic disease, accelerated aging and death.”
“In most cases, pathogenesis-based drugs like insulin for diabetes and statins for dyslipidemia (an imbalance of blood lipids, such as cholesterol, that leads to cardiovascular disease) must be taken for life because the root cause of the chronic symptoms is not changed by treatment.”
In his new paper, Naviaux posits that the root cause of many chronic diseases lies with disruption in the normal sequence of mitochondrial transformations needed to initiate and complete the healing cycle. He has called this universal response to infection, stress, or injury, the cell danger response or CDR. The CDR is an evolutionarily conserved metabolic response that protects cells and hosts from harm. CDR is triggered by exposure to chemical, physical or biological threats. It is a normal part of the immune response that prompts cells to take protective measures.
But sometimes, as Naviaux has shown in past published work, including a ground-breaking preclinical study in 2014, and a seminal Phase 1b/2a Clinical Trial involving young boys with autism published in 2017, CDR continues to sound the alarm even after the originating threat is gone. Inflammation and cell dysfunction persist, resulting in chronic symptoms.
“Abnormal persistence of any phase of the CDR inhibits the healing cycle, creates dysfunctional cellular mosaics, causes the symptoms of chronic disease and accelerates the process of aging,” said Naviaux.
“New research reframes the rising tide of chronic disease around the world as a systems problem caused by the combined action of pathogenic triggers and anthropogenic factors (from human activity, such as pollution) that interfere with the mitochondrial functions needed for healing. Once chronic pain, disability or disease is established, salugenesis-based therapies will start where pathogenesis-based therapies end.”
What is Salugenesis?
Salugenesis derives from the Latin word for the Roman goddess of health, safety and prosperity, Salus. It is related to “salutogenesis,” a word coined in 1976 by the medical sociologist Aaron Antonovsky to describe lifestyle choices and coping skills people use to produce, restore and preserve good health despite all manner of hardship.
Salutogenesis is a sort to big picture concept. Salugenesis is more narrowly focused on the sequential, hard-wired molecular, metabolic and cellular stages of the healing cycle. Both words involve redirecting energy to oppose and reverse the arrow of entropy or decay. They are the opposite of pathogenesis, which is about disorganization and disintegration driven by disease.
Naviaux’s paper makes several key points, among them:
Chronic diseases are currently and mistakenly studied in isolation. Diabetes, for example, looks a lot different from post-traumatic stress disorder. But both, and many other conditions, share an underlying failure of the body to fully heal. “Once the pathogenic trigger has been treated or removed, chronic disease persists because healing is incomplete,” said Naviaux.
Disease is governed by biological logic, which is intrinsic and the result of millions of years of evolution to address internal problems. Modern medicine has advanced through engineering logic, which looks at external issues generally involving non-living systems.
Health and healing are dynamic circles with a beginning, middle and end. The phases are the same whether the injury is a scrape or a stroke. They proceed sequentially by information exchanged between cells and with the environment, directing and informing what happens next. “Mitochondria generate most of the chemical energy needed to power a cell’s biochemical reactions,” said Naviaux. “But they are also cellular canaries in the coal mine, the early warning system that determines the nature and location of a problem or threat, and when to sound the alarm.”
Mitochondria naturally prioritize safety and respond to threats of all kinds—from microbial infections, to physical injury, to chemical pollutants in the air, water, and food chain—by stopping their normal anti-inflammatory functions, and shifting to pro-inflammatory functions needed to contain the damage, replace the cells lost, and finally, to restore normal metabolic communication between cells needed for optimum organ function.
CDR is both alarm and the proportional response to threat, he said. If mitochondria do not function properly — or CDR gets stuck in a phase — healing stops and disease prevails.
Curing chronic disease, according to Naviaux, must account for the fact that all such conditions are systems-wide failures, likely caused by multiple factors. “The same disease can be caused by different things in different people,” said Naviaux. Most diseases involve factors such as multiple genes, infection, environmental or microbial exposures, lifestyle choices and more.
With his work and latest publication, Naviaux argues for development of salugenesis-based research, which would explore the unified biological response to injury, harm and disease. Acute illness, he said, is a temporary state; chronic illness results from the long-term inability to heal completely after an acute injury has passed. They are two sides of the same coin.
Naviaux said he hopes that new research will lead to a “second book of medicine” that will collect new knowledge about the cause and treatment of complex chronic disease viewed through the lens of the healing cycle and salugenesis.
“If healing can be rebooted or unblocked after it has been derailed, cures of disorders once thought incurable may one day be possible,” he said.
Patients’ experiences of health conditions are slowly being integrated into healthcare AI studies, a review of 25 years of studies has found.
In a new paper published in Lancet Digital Health along with an associated opinion piece, experts from the University of Birmingham and University Hospitals Birmingham have looked at more than 600 interventional studies on AI healthcare technologies.
While the team, funded by the National Institute for Health and Care Research (NIHR), found that only 24% of studies have a patient-reported outcome element included in their study, there has been an increase in the number in recent years with 2021 and 2022 seeing nearly two-thirds of all studies included.
Dr Samantha Cruz Rivera from the Centre for Patient Reported Outcomes at the University of Birmingham said:
“The opportunities for AI to revolutionise healthcare will only improve patients’ lives if those models consider how patients actually feel and respond to healthcare interventions. Our review shows that patient reported outcomes, such as measures of symptom burden and quality of life, are increasingly being incorporated into AI studies which is very encouraging.
“The future could see AI healthcare tech analysing and raising an alert if a patient’s health is declining, but such a future is going to depend on having large-scale patient reported outcome datasets so that AI can support or drive care in a specific condition, and incorporate patient experience. Integrating PROs within AI can support the humanisation of AI for health and ensure that the patient’s voice is not lost in a rush to digitise and automate health care.”
Chronic health leading the way
Patient reported outcomes from chronic health conditions such as mental health and arthritis are being adopted into more AI studies than other conditions according to the review.
The research into patient reported outcomes is a key theme of the National Institute for Health and Care Research (NIHR) Birmingham Biomedical Research Centre. The team involved in this paper say that the adoption of PROs for testing AI healthcare technologies in chronic conditions demonstrates how important patient voices are for long-term health management.
Melanie Calvert, Professor of Outcomes Methodology at the University of Birmingham said:
“Managing long term health conditions places a huge burden on patients and their families, but also the NHS and social care system. AI systems can help support patients and healthcare systems to aid decision-making, improve workflow and lead to more efficient care with improved outcomes. Encouragingly, we are seeing more research into AI tech solutions for chronic conditions incorporating patient reported outcomes.
“It’s clear that having technology that can analyse and predict patient outcomes to help prioritise care is going to be a part of healthcare’s future. However, we must ensure that the patient reported outcome data used to train the AI systems are applicable to the population they are intended to serve. If we don’t do this, the gaps between advantaged and disadvantaged populations will only get worse.”
Study offers first glimpse of how many suffer from previously unknown illness
According to a new study, about 13,200 men and another 2,300 women in the United States over age 50 are estimated to have VEXAS syndrome. Long considered a mystery illness until its genetic basis was identified in 2020, the latest findings, led by NYU Grossman School of Medicine researchers, offer the first indication of how common the illness is domestic.
Although a rare disorder, the syndrome carries a high mortality rate, with up to half of people, primarily men, dying within five years of diagnosis. The syndrome most often involves unexplained fevers and low blood oxygen levels in people diagnosed with other diseases, such as rheumatoid arthritis, lupus, and blood cancer. Some symptoms have been linked to an overactive immune system, which can cause inflammation and classify the syndrome as an autoimmune condition.
Researchers hope their findings will raise awareness of the disorder among physicians, particularly because high-dose steroids, JANUS kinase inhibitors, and bone marrow transplantation have proven effective in controlling some symptoms.
“Now that we know VEXAS syndrome is more common than many other types of rheumatologic conditions, physicians need to add this condition to their list of potential diagnoses when confronted by patients with persistent and unexplained inflammation and low blood cell counts, or anaemia,” says geneticist and study lead investigator David Beck, MD, PhD. Beck, an assistant professor in the Department of Medicine and the Department of Biochemistry and Molecular Pharmacology at NYU Langone Health, also led the federal research team initially identifying the shared UBA1 mutation among VEXAS patients.
Statistically, this corresponded to one in 4,269 American men over age 50 and one in 26,238 women over age 50 having or are likely to develop the syndrome. Researchers say this is a higher prevalence figure than many other inflammatory conditions, including vasculitis and myeloid dysplasia syndrome.
“Our study offers the first glimpse of just how common VEXAS syndrome is in the United States, particularly among men, who also happen to be the most to die from it,” says Beck, who is leading several clinical research efforts into VEXAS syndrome at NYU Langone’s Center for Human Genetics and Genomics.
Previous research, led by Beck, traced the syndrome’s origins to a mutation, or change in the letter code that makes up DNA, in the gene UBA1 (short for ubiquitin-like modifier activating enzyme 1.) The enzyme usually assists in protein breakdown.
VEXAS stands for many of its biological characteristics: vacuoles in blood cells, the E1 enzyme, X-linked, autoinflammatory, and somatic.
For the study, researchers analyzed the electronic medical records of adult patients who volunteered to participate in the Geisinger MyCode Community Health Initiative. The program has been collecting data for more than 25 years from patients in Geisinger’s 10-plus hospitals in Central and Northeastern Pennsylvania. Almost all study participants who agreed to have their blood DNA tested were white; half were over the age of 60.
Beck says the team next plans to analyze patient records in more racially diverse groups, especially among those with higher rates of rheumatologic and blood disease, to better understand who is most at risk of VEXAS syndrome. They also plan to look for additional genetic causes, test new therapies for the syndrome, and develop a simple blood test for UBA1 to make it easier to diagnose.
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