Day: October 19, 2023

Females Less Able to Recover from ACL Injuries

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Injuries of the knee’s anterior cruciate ligament (ACL) are typically thought to be caused by acute traumatic events, such as sudden twists. Published in the Journal of Orthopaedic Research, new work analysing an animal model of ACLs suggests that such injuries can also occur as a result of chronic overuse, specifically due to a reduced ability to repair microtraumas associated with overuse. Importantly, the team said, females also are less able to heal from these microtraumas than males, which may explain why females are two to eight times more likely to tear their ACL ligaments than males.

“ACL tears are one of the most common injuries, affecting more than 200 000 people in the US each year, and women are known to be particularly susceptible,” said principal investigator Spencer Szczesny, associate professor of biomedical engineering and of orthopaedics and rehabilitation at Penn State. “While recent research suggests that chronic overuse can lead to ACL injuries, until now, no one had investigated the differential biological response of female and male ACLs to applied force.”

In the Penn State-led study, researchers placed ACLs from deceased male and female rabbits in a custom-made bioreactor that simulated the conditions of a living animal but allowed direct observation and measurement of the tissue. Next, they applied repetitive forces to the ACLs that mimicked those that would naturally occur during activities such as standing, walking and trotting and measured the expression of genes related to healing.

In male samples, the team found that low and moderate applied forces, such as those that would occur during standing or walking, resulted in increased expression of anabolic genes, which are related to building molecules needed for healing. By contrast, larger applied forces, such as those that would occur with repetitive trotting, decreased expression of these anabolic genes. For female samples, however, the amount of force applied did not influence the level of anabolic gene expression.

“It didn’t matter whether there was low, medium or high activity for females,” said Lauren Paschall, graduate student in biomedical engineering at Penn State and first author on the paper. “Female ACLs exposed to chronic use just didn’t heal as well as male ACLs, which may explain why women are predisposed to injuries. This supports the hypothesis that noncontact ACL injuries are attributed to microtraumas associated with chronic overuse that predispose the ACL to injury.”

According to the researchers, one explanation for the sex differences the team observed could be due to the higher amounts of oestrogen in females.

“Some studies have found that the overall effect of oestrogen on ACL injury is negative,” Paschall said. “Specifically, studies have shown that human women are more likely to tear their ACLs during the preovulatory phase, when oestrogen levels are high, than during the postovulatory phase, when oestrogen levels are low.”

She said the team plans to further investigate the role of oestrogen on ACL injury.

Szczesny noted that although the team’s study was not in humans, the findings may suggest that providing additional recovery time for women following injuries could be advantageous.

“Ultimately, this work could also help to identify targets for therapeutics to prevent ACL injuries in women,” he said.

Source: Penn State

Study Finds Urological Effects of SARS-CoV-2 Infection in Men

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A study published in the Journal of Internal Medicine indicates that SARS-CoV-2 infection may worsen lower urinary tract symptoms (LUTS) in men. The study researchers found that a enlarged prostate as a result of COVID was involved.

The study included 17 986 men receiving medication for LUTS within the public healthcare system of Hong Kong in 2021–2022, half of whom had SARS-CoV-2 infection. The group with SARS-CoV-2 had significantly higher rates of retention of urine (4.55% versus 0.86%); blood in the urine (1.36% versus 0.41%); clinical urinary tract infection (4.31% versus 1.49%); bacteria in the urine (9.02% versus 1.97%); and addition of 5-alpha reductase inhibitors, which are drugs prescribed for enlarged prostate. (0.50% versus 0.02%). These urological manifestations occurred regardless of COVID severity.

The findings might relate to the presence of certain proteins targeted by SARS-CoV-2 that are known to be expressed in the prostate.

“We are excited to be the first to report the effects of COVID on complications of benign prostatic hyperplasia – or enlarged prostate – and also demonstrate the alarming extent of its urological effects,” said corresponding author Alex Qinyang Liu, MD, of Prince of Wales Hospital, in Hong Kong.

Source: Wiley

Converting Brain Immune Cells into Neurons Boosts Stroke Recovery in Mice

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Japanese researchers have turned microglia (brain immune cells) into neurons, successfully restoring brain function after stroke-like injury in mice. These findings, published in PNAS, suggest that replenishing neurons from immune cells could be a promising avenue for treating stroke in humans.

Recovery from stroke, where blood supply to neurons is disrupted by blockage or bleeding, is often poor, with patients suffering from severe physical disabilities and cognitive problems.

“When we get a cut or break a bone, our skin and bone cells can replicate to heal our body. But the neurons in our brain cannot easily regenerate, so the damage is often permanent,” says Professor Kinichi Nakashima, from Kyushu University’s Graduate School of Medical Sciences. “We therefore need to find new ways to replace lost neurons.”

One possible strategy is to convert other cells in the brain into neurons. Here, the researchers focused on microglia, the main immune cells in the central nervous system. Microglia are tasked with removing damaged or dead cells in the brain, so after a stroke, they move towards the site of injury and replicate quickly.

“Microglia are abundant and exactly in the place we need them, so they are an ideal target for conversion,” says first author Dr Takashi Irie, from Kyushu University Hospital.

In prior research, the team demonstrated that they could coax microglia to develop into neurons in the brains of healthy mice. Dr Irie and Professor Nakashima and colleagues, now showed that this strategy of replacing neurons also works in injured brains and contributes to brain recovery.

To conduct the study, the researchers caused a stroke-like injury in mice by temporarily blocking the right middle cerebral artery — a major blood vessel in the brain that is commonly associated with stroke in humans. A week later, the researchers examined the mice and found that they had difficulties in motor function and had a marked loss of neurons in a brain region known as the striatum. This part of the brain is involved in decision making, action planning and motor coordination.

The researchers then used a lentivirus to insert DNA into microglial cells at the site of the injury. The DNA held instructions for producing NeuroD1, a protein that induces neuronal conversion. Over the subsequent weeks, the infected cells began developing into neurons and the areas of the brain with neuron loss decreased. By eight weeks, the new induced neurons had successfully integrated into the brain’s circuits.

At only three weeks post-infection, the mice showed improved motor function in behavioural tests. These improvements were lost when the researchers removed the new induced neurons, providing strong evidence that the newly converted neurons directly contributed to recovery.

“These results are very promising. The next step is to test whether NeuroD1 is also effective at converting human microglia into neurons and confirm that our method of inserting genes into the microglial cells is safe,” says Professor Nakashima.

Furthermore, the treatment was conducted in mice in the acute phase after stroke, when microglia were migrating to and replicating at the site of injury. Therefore, the researchers also plan to see if recovery is also possible in mice at a later, chronic phase.

Source: Kyushu University

AI-based CT Scans of the Brain can Nearly Match MRI

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A new artificial intelligence (AI)-based method can provide as much information on subtle neurodegenerative changes in the brain captured by computed tomography (CT) as compared to magnetic resonance imaging (MRI). The method, reported in the journal Alzheimer’s & Dementia, could enhance diagnostic support, particularly in primary care, for conditions such as dementia and other brain disorders.

Compared to MRI, which requires powerful superconducting magnetics and their associated cryogenic cooling, computed tomography (CT) is a relatively inexpensive and widely available imaging technology. CT is considered inferior to MRI when it comes to reproducing subtle structural changes in the brain or flow changes in the ventricular system. Certain imaging must therefore currently be carried out by specialist departments at larger hospitals equipped with MRI.

AI trained on MRI images

Created with deep learning, a form of AI, the software has been trained to transfer interpretations from MRI images to CT images of the same brains. The new software can provide diagnostic support for radiologists and other professionals who interpret CT images.

“Our method generates diagnostically useful data from routine CT scans that, in some cases, is as good as an MRI scan performed in specialist healthcare,” says Michael Schöll, a professor at Sahlgrenska Academy who led the work involved in the study, carried out in collaboration with researchers at Karolinska Institutet, the National University of Singapore, and Lund University

“The point is that this simple, quick method can provide much more information from examinations that are already carried out on a routine basis within primary care, but also in certain specialist healthcare investigations. In its initial stage, the method can support dementia diagnosis, however, it is also likely to have other applications within neuroradiology.”

Reliable decision-making support

This is a well-validated clinical application of AI-based algorithms, and has the potential to become a fast and reliable form of decision-making support that effectively reduces the number of false negatives. The researchers believe that this solution can improve diagnostics in primary care, optimising patient flow to specialist care.

“This is a major step forward for imaging diagnosis,” says Meera Srikrishna, a postdoctor at the University of Gothenburg and lead author of the study.

“It is now possible to measure the size of different structures or regions of the brain in a similar way to advanced analysis of MRI images. The software makes it possible to segment the brain’s constituent parts in the image and to measure its volume, even though the image quality is not as high with CT.”

Applications for other brain diseases

The software was trained on images of 1117 people, all of whom underwent both CT and MRI imaging. The current study mainly involved healthy older individuals and patients with various forms of dementia. Another application that the team is now investigating is for normal pressure hydrocephalus (NPH).

With NPH, the team has obtained new results indicating that the method can be used both during diagnosis and to monitor the effects of treatment. NPH is a condition that occurs particularly in older people, whereby fluid builds up in the cerebral ventricular system and results in neurological symptoms. About two percent of all people over the age of 65 are affected. Because diagnosis can be complicated and the condition risks being confused with other diseases, many cases are likely to be missed.

“NPH is difficult to diagnose, and it can also be hard to safely evaluate the effect of shunt surgery to drain the fluid in the brain,” continues Michael. “We therefore believe that our method can make a big difference when caring for these patients.”

The software has been developed over the course of several years, and development is now continuing in cooperation with clinics in Sweden, the UK, and the US together with a company, which is a requirement for the innovation to be approved and transferred to healthcare.

Source: University of Gothenburg

No Increase in Post-surgical Pain Seen with Opioid Limits

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Concerns that surgery patients would have a more difficult recovery if their doctors had to abide by a five-day limit on opioid pain medication prescriptions did not play out as expected, finds a study published in JAMA Health Forum.

Instead, the University of Michigan-led researchers found that , after the largest insurer in that US state put the limit in place, patient-reported pain levels and satisfaction didn’t change at all for adults who had their appendix or gallbladder removed, a hernia repaired, a hysterectomy or other common operations.

At the same time, the amount of opioid pain medication patients covered by that insurer received dropped immediately after the limit went into effect. On average, patients having these operations received about three fewer opioid-containing pills.

The study, which merges two statewide databases on patients covered by Blue Cross Blue Shield of Michigan, is the first large study to evaluate whether opioid prescribing limits change patient experience after surgery.

Measuring the impact of limits from patients’ perspectives

The BCBSM limit of five days’ supply, which went into effect in early 2018, is even stricter than the seven-days’ supply limit put in place a few months later by the state of Michigan.

Other major insurers and states have also implemented limits, most of which allow are seven-day limits.

Limits are designed to reduce the risk of long-term opioid use and opioid use disorder, as well as to reduce the risk of accidental overdose and the risk of unauthorized use of leftover pills.

“Opioid prescribing limits are now everywhere, so understanding their effects is crucial,” said lead author Kao-Ping Chua, MD, PhD.

“We know these limits can reduce opioid prescribing, but it hasn’t been clear until now whether they can do so without worsening patient experience.”

He noted that even the 15% of patients who had been taking opioids for other reasons before having their operations showed neither an increase in pain nor a decrease in satisfaction after the limit was put in place, even though opioid prescribing for these patients decreased.

That decrease was actually contrary to the intent of the limit, which was only designed to reduce prescribing to patients who hadn’t taken opioids recently.

How the study was done

For the new study, Chua and colleagues used data from the Michigan Surgical Quality Collaborative, which collects data on patients having common operations at 70 Michigan hospitals. The MSQC surveys patients about their pain, level of satisfaction and level of regret after their operations.

The team paired anonymized MSQC data with data on controlled substance prescription fills from Michigan state’s prescription drug monitoring programme, called MAPS.

In all, they were able to look at opioid prescribing and patient experience data from 1,323 BCBSM patients who had common operations in the 13 months before the five-day limit went into effect, and 4,722 patients who had operations in the 20 months after the limit went into effect.

About 86% of both groups were non-Hispanic white, patients’ average age was just under 49,  and just under a quarter of both groups had their operations on an emergency or urgent basis. Just under half were admitted to the hospital for at least one night.

About 27% of both groups had their gallbladders taken out laparoscopically, and a similar percentage had minor hernia repairs.

About 10% had an appendectomy done laparoscopically, and a similar percentage had laparoscopic hysterectomies.

The rest had more invasive procedures, like open hysterectomies major hernia repairs, or colon removal. 

The percentage of prescribers who prescribed opioids to their patients having these operations did not change, but the percentage of patients who filled a prescription for an opioid did, possibly because pharmacists rejected prescriptions that weren’t compliant with the BCBSM limit, Chua speculates.

Jennifer Waljee, MD, MPH, MS, senior author of the study, notes that the MSQC database doesn’t include all types of procedures, such as knee replacements and spine surgery, which typically require larger postoperative opioid prescriptions because of their associated pain.

She indicated that it’s important to understand the impact of opioid prescribing limits on the experiences of such patients, because limits have the most potential to worsen pain for these individuals. 

“Opioid prescribing limits may not worsen patient experience for common, less-invasive procedures like those we studied, because opioid prescriptions for most of these procedures were already under the maximum allowed by limits.

“But this may not be the case for painful operations where opioid prescribing was suddenly cut from an 8- to 10-day supply to a 5-day supply,” said Waljee.

She added, “The message of this study is not that we can simply go to five days’ supply across the board for operations.

“We need to understand the effects of these limits across a broad range of procedures and patients given how much pain needs vary in order to right size prescribing to patient need without resulting in additional harms.”

Source: University of Michigan