Publisher Health

Global Pharma recalled eye drops in February after they were tied to a drug-resistant bacteria strain linked to at least one death. Two more companies have since recalled eye drops.Two brands of eye drops were pulled from shelves in January and February after they were linked to a drug-resistant bacteria strain that has caused at least one person’s death and serious health issues in others. Weeks later, two other types of eye drops were recalled because they posed a different kind of contamination risk.This flurry of recalls may have you second-guessing your trusted source of dry-eye relief, but there are significant differences among the recalls and plenty of steps you can take to stay safe.“I would encourage all people out there who take eye drops to continue using them, of course making sure that they’re not using any of these that are recalled,” said Dr. Christopher Starr, a clinical spokesman for the American Academy of Ophthalmology.Here’s what to know about these recalls.What eye drops have been recalled?In January, the Centers for Disease Control and Prevention and the Food and Drug Administration warned people to stop using EzriCare Artificial Tears and Delsam Pharma’s Artificial Tears after the eye drops were linked to a drug-resistant strain of the bacteria Pseudomonas aeruginosa. Infections from this bacteria strain have caused at least one person’s death, vision loss in eight others and the surgical removal of four people’s eyeballs.Global Pharma, which makes EzriCare and Delsam Pharma’s eye drops, recalled both products in February.Last week, a Florida woman sued Global Pharma, claiming that an infection caused by the eye drops was so severe that doctors had to surgically remove one of her eyes.The F.D.A. has also warned people to stop using an eye ointment manufactured by Global Pharma because of possible contamination.The manufacturer of EzriCare Artificial Tears said it was recalling the product out of “an abundance of caution.”EzriCareThe two other eye drop recalls were not linked to the bacteria outbreak.On March 1, Apotex recalled prescription eye drops used to reduce eye pressure in people with glaucoma or ocular hypertension. The company recalled six lots of Brimonidine Tartrate Ophthalmic Solution 0.15 percent because at least four bottle caps developed cracks, which could affect the product’s sterility.Apotex recalled six lots of Brimonidine Tartrate Ophthalmic Solution 0.15 percent prescription eye drops.via F.D.A.On March 3, Pharmedica recalled two lots of Purely Soothing 15 percent MSM Drops because they were not sterile. These drops are used to treat eye irritation and swelling.Pharmedica recalled two lots of Purely Soothing 15 percent MSM Drops because they were not sterile.via F.D.A.Review the recall notices.The C.D.C. said that, as of March 14, the drug-resistant bacteria strain linked to the recalled EzriCare and Delsam eye drops had been found in 68 people in 16 states.The best way to find out if you have eye drops that were included in the recall is to review the recall notice provided by each company. Each notice has details on which batch of each product was affected.The notice for the EzriCare and Delsam eye drops is here, and the notice for the Global Pharma eye ointment is here. The Apotex Brimonidine Tartate notice is here and the Pharmedica Purely Soothing notice is here.See a doctor if you have symptoms.People who have used these artificial tears and who have symptoms of an eye infection should see a doctor immediately, the C.D.C. said. The symptoms can include yellow, green or clear discharge from the eye, redness of the eye or eyelid, increased sensitivity to light and eye pain or discomfort.Apotex said that people who received its recalled eye drops, which were distributed between April 5, 2022, and Feb. 22, should contact their health care provider and pharmacy. The company also provided a phone number and website for people to request a “recall/return packet.”An Apotex vice president, Jordan Berman, said in an email that the company had seen only four bottles with cracked caps. He said that one of the bottles was from a customer or consumer complaint and the other three were found in retained samples — products that the F.D.A. requires a company to keep back in case issues like these arise.“There have been no drug safety reports related to negative health outcomes due to this product,” Mr. Berman said.Pharmedica said that, as of March 3, it had not received any reports of illness or other “adverse events” from the use of the eye drops. The company did not specify how many bottles were affected or how the bottles became not sterile.Anyone who has issues with any of the recalled the eye drops can file a report with the F.D.A. online, by mail or by fax.Eye drops are generally safe.Dr. Barbara Tylka, an optometrist at the Mayo Clinic in Rochester, Minn., said that, in general, eye drops are safe to use and that many people need them to treat conditions such as dryness or irritation. About 117 million Americans used eye drops and eyewash in 2020, according to Statista, a market research firm.To use eye drops safely, Dr. Tylka said that people should use their own bottle and make sure it has not expired. People who have had eye drops prescribed to them for a procedure such as cataract surgery should stop using those products once the healing process is over, she said.To safely apply eye drops, she said, people should use their nondominant hand to “gently tug on the lower eyelid, look up slightly,” and then, with the dominant hand, put “that little drop in that lower cul-de-sac in the eyelid area.”Dr. Starr, an associate professor of ophthalmology at Weill Cornell Medicine, said that one thing some patients do wrong is press the bottle tip into the inner corner of the eye, which can contaminate the drops and scratch the surface of the eye. He said that when he accidentally hits his eyelid or eyelashes with the bottle tip, he considers the bottle contaminated and either resterilizes it or replaces it.Dr. Starr and Dr. Tylka both emphasized that, while the recalls were worrying, eye drops are generally safe.“I’ve continued to use eyedrops every day throughout this whole thing,” Dr. Starr said.

In a Phase II trial led by researchers from The University of Texas MD Anderson Cancer Center, adding ipilimumab to a neoadjuvant, or pre-surgical, combination of nivolumab plus platinum-based chemotherapy, resulted in a major pathologic response (MPR) in half of all treated patients with early-stage, resectable non-small cell lung cancer (NSCLC).
New findings from the NEOSTAR trial, published today in Nature Medicine, provide further support for neoadjuvant immunotherapy-based treatment as an approach to reduce viable tumor at surgery and to improve outcomes in NSCLC. The combination also was associated with an increase in immune cell infiltration and a favorable gut microbiome composition.
The current study reports on the latest two arms of the NEOSTAR trial, evaluating neoadjuvant nivolumab plus chemotherapy (double combination) and neoadjuvant ipilimumab plus nivolumab and chemotherapy (triple combination). Both treatment arms met their prespecified primary endpoint boundaries of six or more patients achieving MPR, defined as 10% or less residual viable tumor (RVT) in the resected tumor specimen at surgery, a candidate surrogate endpoint of improved survival outcomes from prior studies.
In the intention-to-treat population, the triple combination resulted in an MPR rate of 50%, whereas 32.1% of patients achieved MPR after double combination treatment. Both treatment arms also exceeded the historical MPR rates of 15% achieved by neoadjuvant chemotherapy alone.
“The results we see with neoadjuvant dual immunotherapy and chemotherapy are very encouraging,” said corresponding author Tina Cascone, M.D., Ph.D., assistant professor of Thoracic/Head & Neck Medical Oncology. “This is a population of patients that can potentially be cured, but they need more effective treatment strategies to reduce their risk of disease relapse and improve their outcomes. The NEOSTAR platform provides us with a quick readout of potentially effective regimens and allows us to perform translational analyses and correlative research work before and after treatment.”
Among patients diagnosed with NSCLC, roughly 30% have potentially resectable disease, meaning their tumor can be surgically removed. While many of these patients can potentially be cured with surgery, it is estimated that more than half will have a recurrence without additional therapy. Unfortunately, chemotherapy given either before or after surgery provides only a minimal survival benefit. Previous reports from the NEOSTAR trial demonstrated that neoadjuvant nivolumab plus ipilimumab induced higher MPR rates relative to historical controls of chemotherapy and nivolumab alone and resulted in greater immunological memory relative to nivolumab monotherapy.

Triple combination reduces viable tumor, enhances markers of immune activation Each arm enrolled 22 patients with surgically resectable stage IB to IIIA NSCLC between December 2018 and December 2020. In the double combination arm, participants were 86% White, 14% Asian, and 45% male; in the triple combination arm, participants were 82% White, 5% Asian, 14% Black, and 68% male.
The NEOSTAR trial was not designed for direct comparisons between arms, but an exploratory analysis of clinical and pathological findings showed that adding a single dose of ipilimumab resulted in an increase in beneficial tumor immune cell infiltration and reduced RVT at surgery.
Patients treated with the triple combination had a median of 4.5% RVT at surgery, compared to 50.5% RVT in patients treated with the double combination. All patients achieving MPR in the triple combination cohort and 86% of those achieving MPR in the double combination cohort had less than 5% RVT at surgery. All patients treated with the double combination and 91% of those treated with the triple combination underwent surgery. No new safety signals were observed in both treatment arms.
Further analyses showed treatment with the triple combination resulted in an increase in tumor-infiltrating lymphocytes — including subtypes of CD8+ T cells and B cells and in markers of specialized immune cell clusters called tertiary lymphoid structures, as well as reduced infiltration of immunosuppressive cells, all of which can be signs of enhanced anti-tumor response.
Upon analyzing the gut microbiome in patients who achieved MPR, the researchers found an enrichment in beneficial bacteria previously associated with favorable responses to immunotherapy in lung cancer, melanoma and other cancer types, along with reduced abundance of potentially pathogenic microbes.
NEOSTAR platform is an effective strategy to rapidly test neoadjuvant therapies Interestingly, an exploratory comparison indicates some results from the double combination arm of the NEOSTAR trial are similar overall to those seen in the recent Checkmate-816 trial. This global randomized Phase III study evaluated neoadjuvant nivolumab plus chemotherapy compared to chemotherapy alone in patients with resectable NSCLC, and results from the study led to the first FDA-approved neoadjuvant therapy for NSCLC.
Both Checkmate-816 and NEOSTAR showed similar overall MPR rates and event-free survival benefits from adding neoadjuvant nivolumab to chemotherapy. The similarity between the two trials suggests that the NEOSTAR platform may offer a viable strategy to rapidly evaluate neoadjuvant therapies.
“The modular platform of the NEOSTAR trial provides an opportunity to test promising regimens and quickly make a ‘go’ or ‘no-go’ decision,” Cascone said. “This trial is an incredible testament to the team science environment at MD Anderson. Our clinical and multi-omics analyses were made possible through collaborative efforts from clinicians, surgeons, pathologists, scientists, bioinformaticians and statisticians across several departments looking at many features of these patients and their tumors and other samples. Thanks to their incredible work, we are able to rapidly generate results that could guide the next generation of trials to further improve patient outcomes.”
The results of these latest two arms of the study support the addition of neoadjuvant CTLA-4 blockade to nivolumab plus chemotherapy prior to NSCLC resection for improving outcomes and suggest that this combination merits further investigation.

Criteria used by neurologists to assess for multiple sclerosis (MS) in adults may fail to identify the illness in children with imaging suspicious for the disease, an oversight that could delay treatment of the disease at its earliest stages, according to a Rutgers study.
Magnetic resonance imaging (MRI) is the primary tool used for diagnosis of MS, and doctors have applied various standards over the years to classify those most likely to develop the disease. The most recent standard, known as the McDonald criteria, was last updated in 2017.
In some cases, imaging suspicious for MS is found incidentally before the disease manifests, a condition known as radiologically isolated syndrome (RIS). But after reviewing the MRIs of children with RIS, researchers determined these criteria are likely insufficient for pediatric patients.
“In our study, not all patients met the McDonald or Barkhof criteria [the current standard for diagnosing adult RIS], yet some went on to develop MS,” said Vikram Bhise, director of Child Neurology and Developmental Disabilities at Rutgers Robert Wood Johnson Medical School, and lead author of the study published in the journal Multiple Sclerosis and Related Disorders. “This suggests that the criteria used to characterize RIS in adults might be insufficient for the younger population.”
To determine if children with abnormal MRI findings would develop symptoms associated with MS, and to understand how diagnostic tools used for adults apply to children, researchers examined MR images of children suspected of having demyelination, damage to the protective myelin sheath that surrounds nerve fibers in the brain.
When the myelin sheath is damaged, nerve impulses slow or even stop, causing neurological issues. This damage appears as lesions — white or gray spots — on an MRI. There are many reasons for abnormal MRI findings; most don’t represent demyelination. While not all patients with MRI findings typical of demyelination go on to develop MS, a substantial number do.
Study participants were identified through the U.S. Network of Pediatric Multiple Sclerosis Centers and Rutgers Robert Wood Johnson Medical School databases. Patients were between 7.6 years and 17.8 years of age, and each had MRI findings that showed demyelination.
None of the children in the study had physical or neurological symptoms common to MS — such as blurred or loss of vision, vertigo or numbness or weakness in one or both legs — at the time of their initial MRI. While the database didn’t record why participants had been tested, Bhise said headaches were the most common reason.
After initial review of MRI data, patient data was assessed over a mean duration of 3.7 years to measure development of a first MS attack or new lesions. Of the 38 patients included in the study, 14 of 35 (40 percent) experienced a new clinical attack and 27 of 37 (73 percent) exhibited new MRI lesions during the review period.
When the researchers applied current MS diagnostic measures to the cohort, they found that many patients still developed MS even though they failed to meet either the McDonald or Barkhof criteria.
“Finding MS early can help a doctor knock out a whole bunch of future problems for their patients,” Bhise said. “But that can only happen with accurate diagnostic tools.”
In the U.S., an estimated 1 million people are living with MS, and about 4,000 are under the age of 18, according to MS International Federation, a global network of MS societies.

Using a new computational approach they developed to analyze large genetic datasets from rare disease cohorts, researchers at the Icahn School of Medicine at Mount Sinai and colleagues have discovered previously unknown genetic causes of three rare conditions: primary lymphedema (characterized by tissue swelling), thoracic aortic aneurysm disease, and congenital deafness. The work was done in collaboration with colleagues at the University of Bristol, UK; KU Leuven, Belgium; the University of Tokyo; the University of Maryland; Imperial College London, and others from around the world.
An enhanced understanding of the functions of the genes involved in these and other disorders could pave the way for the development of treatments. The findings were published in the March 16online issue of Nature Medicine.
Rare diseases affect approximately 1 in 20 people, but only a minority of patients receive a genetic diagnosis. Fewer than half of the 10,000 recorded rare diseases have a known genetic cause. Genome sequencing of large cohorts of rare disease patients provides a route toward discovering the genetic causes that remain unknown. However, large genetic datasets are challenging to work with, slowing down research significantly, say the investigators.
“While rare diseases are individually rare, collectively they are quite common. It is important for our understanding of human biology and for the development of diagnostics and therapeutics that the remaining causes are found,” said senior study author Ernest Turro, PhD, Associate Professor of Genetics and Genomics Sciences at Icahn Mount Sinai. “Many people with a rare disease struggle for many years to obtain a genetic diagnosis. By developing and applying statistical methods and computational approaches to find new causes of rare diseases, we hope to expand knowledge of the underlying causes of these diseases, hasten the time to diagnosis for patients, and pave the way for the development of treatments.”
The investigators studied a collection of 269 rare disease classes using data from 77,539 participants in the 100,000 Genomes Project, one of the largest datasets of phenotyped and whole-genome-sequenced rare disease patients. The researchers identified 260 associations between genes and rare disease classes, including 19 associations previously absent from the literature. Through an international academic collaboration, the authors validated the three most plausible novel associations by identifying additional cases in other countries and through experimental and bioinformatic approaches.
“We hope that our computational framework will help accelerate the discovery of the remaining unknown etiologies of rare diseases across the board. For now, we expect that a genetic diagnosis will be attainable for certain families with previously unexplained primary lymphedema, thoracic aortic aneurysm disease, and deafness,” said Daniel Greene, PhD, a postdoctoral fellow at Icahn Mount Sinai and lead author of the study. “We also plan to apply our methods in novel ways and in other datasets, with the aim of continuing to unravel the genetic causes of rare diseases.”

Preterm infants do not get used to repeated pain in the way that full-term infants, children and adults do habituate to pain, finds a study led by UCL (University College London) researchers.
The authors of the new Current Biology paper say that if preterm infants have not yet developed the mechanism that enables people to get used to moderate pain, medical procedures in their first few weeks of life could potentially impact their development.
Lead author Dr Lorenzo Fabrizi (UCL Neuroscience, Physiology & Pharmacology) said: “The way that we can get used to things can be seen as the simplest example of behavioural and brain plasticity, and it is a basic part of memory and learning. Pain habituation is important because it enables us to preserve physical, emotional, and cognitive resources by not overreacting to pain that is unavoidable or not life-threatening.
“Our findings suggest that the ability to get used to repeated pain might develop during the third trimester of pregnancy, so that babies born prematurely have not yet developed this ability that full-term babies have right from birth.”
The study involved 20 infants at University College London Hospitals (UCLH). Half of them were preterm (and tested while still younger than 35 weeks gestational age*), while the other half were either born at full term (seven infants) or preterm but tested at term age (three infants). The two groups were comparable in terms of their actual postnatal age, as the preterm babies had a median age of 14 days, compared to 10 days among the full-term (or term age) group.
The researchers were measuring the infants’ responses to a painful but clinically required heel lance (blood test), which was conducted twice (three to 18 minutes apart) for each infant (two lances are sometimes required to collect enough blood; this is not needed for most infants so only those that needed a second lance were included in the study).

Heel lances can elicit substantial pain responses in infants, but it was not previously known whether this decreases on repeated lances. To understand this, the researchers recorded the infants’ brain activity with EEG (electroencephalography) electrodes placed on the scalp, and their heart rates using ECG (electrocardiography), while also monitoring their facial expressions and reflexes in withdrawing the leg.
The researchers found that the brain activity was not as strong immediately after the second heel lance, compared to the first, suggesting a habituation response, but this was only the case for full-term infants. They found a similar pattern for heart rate and facial expressions, as preterm infants reacted just as strongly to both heel lances, while the full-term infants appeared to habituate to the pain.
The team says this habituation response might be due to the full-term infants anticipating the imminent pain when they receive a second heel lance, so their reaction is less pronounced, or it may instead or additionally be due to their brains modulating their reflexive survival responses.
They add that habituation to pain might protect the full-term infants, but not those who were pre-term, from potential consequences to their development.
First author Dr Mohammed Rupawala (UCL Neuroscience, Physiology & Pharmacology) said: “While unpleasant and painful clinical procedures are necessary for many young infants, there is the potential to impact their development, such as by altered pain perception, or potentially reduced grey matter or disrupted white matter in the brain.”
Co-author Dr Judith Meek, consultant neonatologist at UCLH, said: “This work raises awareness of the extra vulnerability of premature babies to pain. Clinicians need to do their best to protect them from repeated painful experiences. This should be regarded as an essential component of brain oriented newborn care.”
The study, funded by the Medical Research Council and the European Research Council, involved researchers at UCL, UCLH and York University (Canada).
* Gestational age refers to the weeks elapsed since the start of the mother’s last menstrual cycle. The 10 infants classified as preterm in this study had a median gestational age of 31 weeks, so they were still in developmental stages normally undergone while still in the womb.

A small nucleus in the brainstem called locus coeruleus (literally the “blue spot,”) is the primary source of a major neuromodulator, norepinephrine (NE), an important mediator of the ‘fight or flight’ response in animals. However, very little is known about the local connections of this small albeit critically important group of neurons. A recent pioneering study published in eLife from the laboratory of Dr. Xiaolong Jiang, investigator at the Jan and Dan Duncan Neurological Research Institute (Duncan NRI) at Texas Children’s Hospital and assistant professor at Baylor College of Medicine, now reveals the cellular composition and circuit organization of the locus coeruleus in adult mice.
“In this study, we undertook the arduous task of mapping local connections of NE-producing neurons in the locus coeruleus,” Dr. Jiang said. “This is the first study of such an unprecedented magnitude and detail to be performed on the locus coeruleus, and in fact, on any monoamine neurotransmitter system. Our study has revealed that the neurons in the locus coeruleus have an unexpectedly rich cellular heterogeneity and local wiring logic.”
Locus coeruleus senses danger and alerts other brain regions
Locus coeruleus (LC) is known to house the vast majority of norepinephrine-releasing neurons in the brain and regulates many fundamental brain functions including the fight and flight response, sleep/wake cycles, and attention control. Present in the pontine region of the brainstem, LC neurons sense any existential dangers or threats in our external environment and send signals to alert other brain regions of the impending danger.
The primary action of LC neurons is to release norepinephrine, a neurotransmitter, and a hormone, that increases alertness and promotes arousal, regulating the sleep/wake cycle and memory. Altered levels of norepinephrine are associated with depression, anxiety, post-traumatic stress disorder, panic attacks, hyperactivity, heart problems, and substance abuse. Thus, a better understanding of how LC neurons function is key to understanding and identifying therapies for many neuropsychiatric and neurodegenerative conditions.
Locus coeruleus has two distinct cellular subtypes, homotypically connected via gap junctions
Once viewed as a homogenous group of neurons that exert global, uniform influence over the entire brain, recent studies suggest LC neurons are a heterogeneous population of noradrenergic cells that exhibit both spatial and temporal modularity. These findings piqued the interest of Dr. Jiang and his team to investigate the cellular and circuit mechanisms underlying the functional diversity of LC neurons.

To do that, the team had to overcome a few technical barriers to be able to measure the activity of several LC neurons simultaneously from the brain slices of adult mice. For instance, while the technique of intracellular recordings of more than two neurons simultaneously has been used to study cortical circuits for the past few decades, it has been challenging to use this technique to record small nuclei in the brainstem such as the LC due to the space restraint and limited cell number in each brain slice. In this study, by optimizing slice quality and adapting their recording system to small brainstem slices, Andrew McKinney, a graduate student in the Jiang lab and the first author of the paper, successfully managed to record up to eight LC neurons simultaneously for the first time.
This technical development led Andrew and others in the team to make several unexpected observations about how LC neurons are organized and how they function.
First, consistent with emerging views in the field they found that norepinephrine-producing neurons in the LC are diverse. Further, they found that these can be classified into at least two major cell types based on their morphology and electrical properties and these subtypes occupy different spatial locations (anatomical niches) within LC. This finding provided a solid and much-needed basis for further in-depth studies of LC in adult animals.
Second, they found that LC neurons do not form chemical synapses, the most common type of connection between neurons. Instead, they form electrical synapses and connect to one another via gap junctions. This was an unexpected discovery because the conventional thinking is that electrical coupling via gap junctions is primarily present in developing LC and not in the LC of adult animals.
Third, they found that LC neurons of the same subtype electrically connected with one another but did not connect with the neurons of the other kind, providing the first cellular and circuit clue for the functional modularity of the LC and opening up avenues to understand how functional modularity arises within the noradrenergic system and dynamically controls diverse processes. These findings indicate that given that each cell type has preferential anatomical locations in LC and different projection targets, each electrically coupled within-cell-type homotypic network may coordinate or synergize their input or output as a whole to engage in distinct functions of the circuits as they carry information from the brain to various targets such as muscles or glands.
Finally, unlike the web-like connections that are typical of chemical synapses between neurons in the central nervous system, LC neurons of a single subtype were discovered to form unique linear chain-like electrical connections with one another. This provides the first experimental clue into how electrically-coupled neuronal networks are organized in the brain.
“This study sheds light on several unexplored questions about the cellular and circuit organization of the locus coeruleus in particular and also offers several new insights into other broader aspects of brain physiology,” Dr. Jiang said. “We anticipate these novel findings will be of broad interest to cellular, systems, and computational neuroscientists and will inspire several future studies to understand how each neuron within LC interacts with one another to give rise to a synchronized network,” Dr. Jiang added. “In addition, given that the dysregulation of the LC has been implicated in many neuropsychiatric and neurodegenerative disorders including autism and Alzheimer’s disease, these findings provide an essential knowledge base to decipher cellular and circuit mechanisms of these diseases.”
Others involved in the study were Ming Hu, Amber Hoskins, Arian Mohammadyar, Nabeeha Naeem, Junzhang Jing, Saumil Patel, and Bhavin Sheth. They are affiliated with one or more of the following institutions: Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, Baylor College of Medicine, and the University of Houston. The study was supported by several research and training grants from the National Institutes of Health and the Main Street America Fund.

Sleeping less than five hours a night is associated with a 74% raised likelihood of developing peripheral artery disease (PAD) compared with seven to eight hours. That’s the finding of a study published today in European Heart Journal — Open, a journal of the ESC.1
“Our study suggests that sleeping for seven to eight hours a night is a good habit for lowering the risk of PAD,” said study author Dr. Shuai Yuan of the Karolinska Institute, Stockholm, Sweden.
More than 200 million people globally have peripheral artery disease (PAD),2 where arteries in the legs are clogged, restricting blood flow and increasing the risk of stroke and heart attack. Dr. Yuan said: “Insufficient night-time sleep and daytime napping have previously been associated with a raised risk of coronary artery disease which, like PAD, is caused by clogged arteries. In addition, sleeping problems are among the top ranked complaints in PAD patients. There are limited data on the impact of sleep habits on PAD and vice versa, and our study aimed to fill that gap.”
The study included more than 650,000 participants and was conducted in two parts.3 First, the researchers analysed the associations of sleep duration and daytime napping with the risk of PAD. In the second part, the investigators used genetic data to perform naturally randomised controlled trials — called Mendelian randomisation — to examine causality of the associations.
Dr. Yuan said: “Observational analyses are limited by reverse causality — meaning that if an association between sleep habits and PAD is found, we cannot be certain if sleep habits caused PAD or having PAD caused the sleep habits. Mendelian randomisation is a robust method for evaluating causality and provides more certainty about the results.”
Taken together, the strongest evidence was for short sleep, where the relationship with PAD went both ways. In an observational analysis of 53,416 adults, sleeping less than five hours a night was associated with a nearly doubled risk of PAD compared with seven to eight hours (hazard ratio [HR] 1.74; 95% confidence interval [CI] 1.31-2.31). This finding was supported by further analyses in 156,582 and 452,028 individuals. In the causal studies, short sleep was associated with an increased risk of PAD and, in addition, PAD was associated with an increased likelihood of short sleep. Dr. Yuan said: “The results indicate that brief night-time sleep can raise the chance of developing PAD, and that having PAD increases the risk of getting insufficient sleep.”
Regarding long sleep, in an observational analysis of 53,416 adults, sleeping eight hours or more per night was linked with a 24% higher risk of PAD compared with seven to eight hours (HR 1.24; 95% CI 1.08-1.43). This finding was supported by analyses in two larger populations of 156,582 and 452,028 individuals. However, no causal relationships were found between long sleep and PAD. Similar results were reported for napping, where daytime nappers had a 32% higher risk of PAD compared to those who did not nap (HR 1.32; 95% CI 1.18-1.49) but no causal links were found. “More studies are needed on the relationships between lengthy night-time sleep, daytime napping and PAD,” said Dr. Yuan. “Although we found associations in the observational studies, we could not confirm causality.”
He concluded: “More research is needed on how to interrupt the bidirectional link between short sleep and PAD. Lifestyle changes that help people get more sleep, such as being physically active, may lower the risk of developing PAD. For patients with PAD, optimising pain management could enable them to have a good night’s sleep.”

Heavy workloads make employees feel a greater need for a break, but new research finds they may actually discourage employees from taking breaks at work despite causing high levels of stress, fatigue, and poor performance.
Researchers from the University of Waterloo found employees often kept working despite wanting to pause. One potential reason is employees may have felt pressure to continue working to get everything done on time.
“Our research provides a comprehensive account of the processes involved in the decision to take a break and provides insights into how employees and managers can make more effective use of breaks at work, potentially improving both well-being and performance,” said James Beck, professor of industrial and organizational psychology at Waterloo.
To conduct the study, researchers asked 107 employees about their reasons for taking a break and not taking one. They then surveyed another 287 employees twice daily over five days about their sleep quality, fatigue, performance concerns, workload, and the number of breaks they take each day.
The researchers also found that although previous research has shown that breaks can benefit employee well-being and performance, they may resist taking breaks if they feel supervisors discourage breaks in their workplace. Although there may be a misconception that breaks are unproductive, Phan notes that many employees take breaks because they are committed to staying focused and maintaining high levels of performance.
“We recognize that it may not always be possible for employees to take more breaks, but if employers can promote employee well-being by addressing the conditions that can make work unpleasant, they may be able to reduce the number of breaks needed,” said Dr. Vincent Phan, first author of the study, which he led as part of his doctoral thesis in industrial and organizational psychology at Waterloo.
The researchers hope that their findings will aid in promoting employee well-being and that future research will explore broader structural and contextual factors that influence break-taking.

A team of scientists led by Dr. Kei-ichi TAKATA from the Center for Genomic Integrity (CGI) within the Institute for Basic Science (IBS), has discovered a new type of DNA repair mechanism that cancer cells use to recover from next-generation cancer radiation therapy.
Ionizing radiation (IR) therapy is frequently used in the treatment of cancer and is believed to destroy cancer cells by inducing DNA breaks. The newest type of radiation therapy harnesses radiation produced by a particle accelerator, which consists of charged heavy particles such as carbon ions. The particle accelerator accelerates the carbon ions to about 70% of the speed of light, which collides with and destroys the DNA of cancer cells.
These ions have a high linear energy transfer (LET) and release most of their energy within a short range, called the Bragg peak. The next-generation cancer radiotherapy works by focusing the Bragg peak on the tumor, which has the added benefit of minimizing damage to surrounding normal tissues compared to the commonly used low LET radiation such as gamma or x-rays.
Only a handful of medical facilities in the world currently possess the capability to deliver this next-generation radiation therapy, although more are hoped to be deployed in the future.
DNA lesions generated by heavy ion bombardment (high LET radiation) are more “complex” than those induced by traditional radiation therapy (low LET radiation). The former carries additional DNA damage such as apurinic/apyrimidinic (AP) site and thymine glycol (Tg) in close proximity to the double-strand breaks (DSB) sites, which is far more difficult to repair than ordinary DNA damage. As a result, the advanced therapy is more cytotoxic per unit dose than low LET radiation.
This makes next-generation radiation therapy a potent weapon against cancer cells. However, it has not been fully investigated how these high LET-induced lesions are processed in mammalian cells, as DNA damage from heavy ion bombardment is a process that seldom occurs in nature (e.g., higher chance in outer space). Figuring out the complex DSB repair mechanism is an attractive research interest since blocking the cancer cells’ repair mechanism can allow the new radiation therapy to become even more effective.

In order to conduct research, the IBS team visited the QST hospital in Japan to use the synchrotron named HIMAC (Heavy Ion Medical Accelerator in Chiba), which has the ability to produce high LET radiation. A similar synchrotron has been installed at Yonsei University and another one is scheduled to be installed at Seoul National University Hospital in Kijang in 2027. Dr. Takata’s research team intends to help establish a basic research program using these synchrotrons in South Korea to improve heavy ion therapy in cancer patients.
Dr. Takata’s research team discovered that DNA polymerase θ (POLQ) is an important factor when repairing complex DSBs such as those caused by heavy-ion bombardment. POLQ is a unique DNA polymerase that is able to perform microhomology-mediated end-joining as well as translesion synthesis (TLS) across an abasic (AP) site and thymine glycol (Tg). This TLS activity was found to be the biologically significant factor that allows for complex DSB repair.
Ms. SUNG Yubin, one of the joint first authors, explains, “We provided evidence that the TLS activity of POLQ plays a critical role in repairing hiLET-DSBs. We found that POLQ efficiently anneals and extends substrates mimicking complex DSBs” .
The researchers also discovered that preventing the expression of POLQ in cancer cells greatly increased their vulnerability to the new radiation treatment.
“We demonstrated that genetic disruption of POLQ results in an increase of chromatid breaks and enhanced cellular sensitivity following treatment with high LET radiation,” explains Mr. YI Geunil, another joint first author .
The research team used biochemical techniques and Fluorescence Resonance Energy Transfer (FRET) to find out that POLQ protein can effectively repair synthetic DNA molecules that mimic complex DSB. This means that POLQ can be a possible new drug target to increase the cancer cells’ vulnerability against complex radiation damage.
The single-molecule FRET assay system to monitor POLQ-mediated annealing and DNA extension was developed in collaboration with Prof. KIM Hajin and Mr. KIM Chanwoo at UNIST. Ms. RA Jae Sun at IBS-CGI analyzed chromatid breaks induced by high LET radiation. Prof. FUJIMORI Akira and Mr. HIRAKAWA Hirokazu at QST, and Prof. KATO Takamitsu at Colorado State University helped conduct the experiments with HIMAC.
Prof. Takata notes, “We are proud to announce the publication of our paper which was only possible through the great teamwork of everybody involved. Our findings provide new insights into the mechanisms of how hiLET-DSB is repaired in mammalian cells and further suggest that the inhibition of POLQ may augment the efficacy of heavy ion radiation therapy.”
This work was published in Nucleic Acids Research on February 20, 2023.

University of Helsinki and Taiwanese researchers have found a new way to remove waste from the brain after haemorrhage.
Intracerebral haemorrhage, and bleeding into the brain tissue, is a devastating neurological condition affecting millions of people annually. It has a high mortality rate, while survivors are affected by long-term neurological deficits. No medication has been found to support brain recovery following hemorrhage.
In an international collaboration, researchers from the Brain Repair laboratory, University of Helsinki, together with their Taiwanese colleagues investigated whether a protein called cerebral dopamine neurotrophic factor (CDNF) has potential as a treatment for brain hemorrhage.
Researchers suggest that cerebral dopamine neurotrophic factor, a protein being currently tested for Parkinson’s disease treatment, also has therapeutic effects and enhances immune cell’s response after brain haemorrhage.
The authors found that the administration of cerebral dopamine neurotrophic factor accelerates hemorrhagic lesion resolution, reduces brain swelling, and improves functional outcomes in an animal model of brain hemorrhage.
“Surprisingly, we found that cerebral dopamine neurotrophic factor acts on immune cells in the bleeding brain, by increasing anti-inflammatory mediators and suppressing the production of the pro-inflammatory cytokines that are responsible for cell signalling. This is a significant step towards the treatment of injuries caused by brain haemorrhage, for which we currently have no cure,” says Professor Mikko Airavaara, from University of Helsinki.
Dr. Vassileios Stratouliasfrom the Brain Repair laboratory comments, “It’s interesting to note that after a bleeding episode, the brain contains a lot of waste and debris. Cerebral dopamine neurotrophic factor encourages immune cells in the brain to consume and remove the waste and debris, which is essential for the brain’s recovery!.”
The administration of cerebral dopamine neurotrophic factor also resulted in the alleviation of cell stress in the area that surrounds the hematoma.
Finally, the researchers demonstrated that systemic administration of cerebral dopamine neurotrophic factor promotes scavenging by the brain’s immune cells after brain haemorrhage and has beneficial effects in an animal model of brain haemorrhage.