Day: April 4, 2022

Fall in Paediatric Post-surgical Opioid Prescriptions

Photo by Ben Wicks on Unsplash

A large study has shown that opioid prescriptions for children who underwent one of eight common outpatient surgeries declined over a period of five years. These findings, reported in the journal Pediatrics, suggest that clinicians are using more discretion when considering which paediatric patients require an opioid prescription after their procedures.

Opioids are routinely prescribed after a surgery to help paediatric patients manage mild or moderate pain. However, recent studies have suggested that recovery is similar with limited or no opioid use. Additionally, opioids prescribed to children can result in respiratory depression, which causes carbon dioxide to not be expelled from the lungs properly, and the continued use of those opioids, after acute pain has resolved. Despite these findings, no prior studies had looked at recent data on national opioid trends for surgery in children in the context of whether there has been any shift away from prescribing opioids more broadly.

“Children grow throughout their childhood, and because opioids are often prescribed based on weight, we cannot assume that what is appropriate for a 5-year-old could also apply to an adolescent,” said the study’s lead author Tori N. Sutherland, MD, MPH. “In our study, we wanted to be responsible with our data and consider surgical distribution by age group.”

In this study, the researchers used data from a private insurance database to study opioid-naïve patients under the age of 18 who underwent one of eight surgical procedures between 2014 and 2019. The procedures ranged from tonsillectomies to knee surgery. The primary outcome of the study was whether a prescription for opioids was filled within 7 days of surgery, and the secondary outcome was the total amount of opioid dispensed. A total of 124 249 patients were included in the study. Patients were separated by age into adolescents, school-aged children and preschool-aged children.

The researchers found that the percentage of children who had an opioid prescription filled after their surgery fell across all three age categories. For adolescents, prescriptions dropped from 78.2% to 48%; for school-aged children, from 53.9% to 25.5%; and for preschool-aged children, from 30.4% to 11.5%. Additionally, the average morphine milligram equivalent dispensed declined by approximately 50% across all three age groups.

The researchers also found that there was a steeper decline in opioid prescriptions beginning in late 2017, first in the adolescent group and then followed by school- and preschool-aged children. This trend appeared to represent a ‘trickle down’ effect, but more research is needed to explore the difference in trends by age group.

“Our findings demonstrate that pain treatment for children and adolescents undergoing surgery has changed dramatically over the past 5 years,” said Mark Neuman, MD, senior author. “Understanding what these trends mean for patient experiences and health outcomes is a key next step.”

Source: EurekAlert!

Possible Cause of COVID Arrhythmias Discovered

Anatomical model of a human heart
Photo by Robina Weermeijer on Unsplash

The SARS-CoV-2 virus can infect cardiac pacemaker cells, causing the cells to undergo self-destruct by ferroptosis according to a preclinical study reported in Circulation Research. This may explain the heart arrhythmias that are commonly observed in COVID patients.

In the study, the researchers used an animal model as well as human stem cell-derived pacemaker cells to show that SARS-CoV-2 can readily infect pacemaker cells and trigger a process called ferroptosis, where cells self-destruct, releasing damaging reactive oxygen molecules.

“This is a surprising and apparently unique vulnerability of these cells — we looked at a variety of other human cell types that can be infected by SARS-CoV-2, including even heart muscle cells, but found signs of ferroptosis only in the pacemaker cells,” said study co-senior author Professor Shuibing Chen.

Arrhythmias, including tachycardia and bradycardia, has been observed in some COVID patients, and multiple studies link these arrhythmias to worse COVID outcomes. But how the coronavirus caused these remained unclear.

In the new study, the researchers examined golden hamsters (one of the only lab animals that reliably develops COVID-like signs from SARS-CoV-2 infection) and found evidence that following nasal exposure, the virus can infect the sinoatrial node, which is the natural cardiac pacemaker.

The researchers then induced human embryonic stem cells to mature into cells closely resembling sinoatrial node cells. They showed that these induced human pacemaker cells can be infected by SARS-CoV-2 as they express ACE2 receptors. Large increases in inflammatory immune gene activity were also seen in the infected cells.

The team’s most surprising finding, however, was that the pacemaker cells, in response to the stress of infection, showed clear signs of a cellular self-destruct process called ferroptosis, which involves accumulation of iron and the runaway production of reactive oxygen molecules. The scientists were able to reverse these signs in the cells using compounds that are known to bind iron and inhibit ferroptosis.

“This finding suggests that some of the cardiac arrhythmias detected in COVID patients could be caused by ferroptosis damage to the sinoatrial node,” said co-senior author Dr Robert Schwartz

While COVID patients could in principle be treated with ferroptosis inhibitors specifically to protect sinoatrial node cells, antiviral drugs that block the effects of SARS-CoV-2 infection in all cell types would be preferable, the researchers said.

The researchers plan to continue to use their cell and animal models to investigate sinoatrial node damage in COVID and other settings.

“There are other human sinoatrial arrhythmia syndromes we could model with our platform,” said co-senior author Dr. Todd Evans. “And, although physicians currently can use an artificial electronic pacemaker to replace the function of a damaged sinoatrial node, there’s the potential here to use sinoatrial cells such as we’ve developed as an alternative, cell-based pacemaker therapy.”

Source: Weill Cornell Medicine

Mental Processing of Autistic and Non-autistic People is Similar

Source: Pixabay

Findings published in Journal of Psychopathology and Clinical Science reveal there are fundamental similarities between autistic and non-autistic people in mental processing. The study findings were made available online ahead of ahead of World Autism Day on the 2nd of April.

The brain uses two systems to process information: System 1 for quicker intuitive judgements, and System 2 for slower rational thinking. In autistic people, these systems are thought to work differently ad underlie difficulties they may have in daily life and the workplace.

Yet, this landmark study reports that these fundamental psychological systems are not impaired in autistic people as once thought. The study, involving more than 1000 people, tested the link between autism and ‘quick’ intuitive and ‘slow’ rational thinking.

In three experiments, they analysed the link between autistic personality traits and thinking style. In the fourth, they compared 200 autistic and over 200 non-autistic people. Overall, their results showed that autistic people think as quickly and as rationally as non-autistic people.

Based on these findings, the researchers conclude that certain, fundamental mental processes are more similar between autistic and non-autistic people than prior belief. In light of these findings, they call for a shift in the way that society thinks about autism as a mental processing disorder.

They also recommend that it might be important to redesign educational, clinical, and workplace support for autistic people and their families. Support should be much more targeted, instead of assuming that autistic people all have mental processing difficulties, they say.

The research team argue that the requirement to make ‘reasonable adjustments’ such as allowing extra time in exams and extending deadlines, is not an evidence-based way to support neurodivergent people.

Instead, more fundamental changes could be necessary – for example, changing social and sensory environments, making them more equitable autistic people.

Source: University of Bath

‘Gene Silencing’ Therapy Cuts Lipoprotein(a) by Up to 98%

DNA repair
Source: Pixabay/CC0

Findings from a new show that an experimental ‘gene silencing’ therapy reduced blood levels of lipoprotein(a) by up 98%. This is significant as lipoprotein(a) is a key cardiovascular risk driver which is determined largely by genetics and not modifiable lifestyle factors, and which cannot be lowered by current medical means.

Findings from the Cleveland Clinic-led phase 1 trial were published in the Journal of the American Medical Association.

Trial participants receiving higher doses of SLN360 – a small interfering RNA (siRNA) therapeutic that ‘silences’ the gene responsible for lipoprotein(a) production – saw their lipoprotein(a) levels  drop by as much as 96%-98%. Five months later, these participants’ lipoprotein(a) – also known as Lp(a) – levels remained 71%-81% lower than baseline.

The findings suggest this siRNA therapy could be a promising treatment to help prevent premature heart disease in people with high levels of Lp(a), which is estimated to affect 64 million people in the United States and 1.4 billion people worldwide.

“These results showed the safety and strong efficacy of this experimental treatment at reducing levels of Lp(a), a common, but previously untreatable, genetically-determined risk factor that leads to premature heart attack, stroke and aortic stenosis,” said the study’s lead author Steven E. Nissen, MD “We hope that further development of this therapy also will be shown to reduce the consequences of Lp(a) in the clinical setting through future studies.”

Lp(a) has similarities to LDL. Lp(a) is made in the liver, where an extra protein called apolipoprotein(a) is attached to an LDL-like particle. Unlike other types of cholesterol particles, Lp(a) levels are 80 to 90% genetically determined. The structure of the Lp(a) particle causes the accumulation of plaques in arteries, which play a significant role in heart disease. Elevated Lp(a) greatly increases the risk of heart attacks and strokes.

Although cardiovascular risk-reduction therapies that lower LDL cholesterol and other lipids exist, there are treatments to lower Lp(a). Since Lp(a) levels are genetically determined, lifestyle changes such as diet or exercise have no effect. In the current study, the siRNA therapy reduces Lp(a) levels by “silencing” the gene responsible for Lp(a) production and blocking creation of apolipoprotein(a) in the liver.

In the APOLLO trial, researchers enrolled 32 participants with Lp(a) levels above 15 nmol/L, with a median level of 224nmol/L (75nmol/L or less is considered normal). Eight participants received a placebo and the remaining received one of four doses of SLN360 via a single subcutaneous injection. The doses were 30mg, 100mg, 300mg and 600mg. Participants were closely observed for the first 24 hours after their injection and then followed up for five months.

Compared to baseline, participants receiving 300mg and 600mg of SLN360 experienced a maximum of 96% and 98% reduction in Lp(a) levels, and a reduction of 71% and 81% at five months. Those receiving a placebo saw no change in Lp(a) levels. The highest doses also reduced LDL cholesterol by about 20%-25%. There were no major safety consequences reported and the most common side effect was temporary soreness at the injection site. The study was extended and researchers will continue to follow participants for a total of one year.

Source: Cleveland Clinic

High Lipid Levels Even More Damaging than Previously Believed

Blood sample being drawn
Photo by Hush Naidoo Jade Photography on Unsplash

High lipid levels in people with type 2 diabetes and obesity are more harmful than previously thought, according to findings from a new study which found that stressed cells can damage nearby cells.

In patients with metabolic diseases, elevated lipid levels in the blood create stress in muscle cells – a reaction to changes outside the cell which damage their structure and function.

The study, published in Nature Communications, shows that these stressed-out cells give off a signal which can be passed on to other cells.

The signals, known as ceramides, may confer a short-term protective benefit, because they are part of a mechanism designed to reduce stress in the cell. But in long term conditions such as metabolic diseases, the signals can actually kill the cells and worsen symptoms and the illness.

High lipid levels have long been known to damage tissues and organs, contributing to the development of cardiovascular and metabolic diseases including type 2 diabetes, a condition which can be caused by obesity.

Professor Lee Roberts, who supervised the research, said: “Although this research is at an early stage, our discovery may form the basis of new therapies or therapeutic approaches to prevent the development of cardiovascular and metabolic diseases such as diabetes in people with elevated blood fats in obesity.”

In the lab, the team replicated the blood lipid levels observed in humans with metabolic disease by exposing skeletal muscle cells to palmitate, a fatty acid. The cells began to transmit the ceramide signal.

When these cells were mixed with others which had not been previously exposed to lipids, the researchers found that they communicated with each other, transporting the signal in packages called extracellular vesicles.

The experiment was reproduced in human volunteers with metabolic diseases and gave comparable results. The findings provide a completely new angle on how cells respond to stress, with important consequences for our understanding of certain metabolic diseases including obesity.

Professor Roberts said: “This research gives us a novel perspective on how stress develops in the cells of individuals with obesity, and provides new pathways to consider when looking to develop new treatments for metabolic diseases.

“With obesity an ever-increasing epidemic, the burden of associated chronic disease such as type 2 diabetes necessitates new treatments. We hope the results of our research here open a new avenue for research to help address this growing concern.”

Source: University of Leeds